Metabolism of lipids: digestion, absorption, resynthesis in the intestinal wall. Metabolism of
lipids: oxidation and biosynthesis of fatty acids, triacylglycerols and
phospholipids. Biosynthesis and biotransformation of cholesterol. Metabolism of
ketonе bodies. Regulation and disorders of lipid metabolism.
Lipids are water-insoluble organic biomolecules
that can be extracted from cells and tissues by nonpolar solvents, e.g.,
chloroform, ether, or benzene.
Lipids
are an amphiphilic class of hydrocarbon-containing organic compounds. Lipids are
categorized by the fact that they have complicated solvation properties, giving
rise to lipid polymorphism. Lipid molecules have
these properties because they consist largely of long hydrocarbon tails which are lipophilic in nature as well as
polar headgroups (e.g. phosphate-based functionality, and/or inositol based functionality).
In living organisms, lipids are used for energy storage, serve as the
structural components of cell membranes, and constitute
important signalling molecules. Although the term
lipid is often used as a synonym for fat, the latter is in fact
a subgroup of lipids called triglycerides.
There are several different families or classes of lipids but all derive
their distinctive properties from the hydrocarbon nature of a major portion of
their structure.
Biological functions of lipids
Biological molecules
that are insoluble in aqueous solutions and soluble in organic solvents are
classified as lipids. The lipids of physiological importance for humans have
four major functions:
Lipids have several important
biological functions, serving
(1) as structural components of membranes,
(2) as storage and transport forms of metabolic fuel,
(3) as a protective coating on the surface of many
organisms, and
(4)
(5) as cell-surface components concerned in cell
recognition, species specificity, and tissue immunity. Some substances
classified among the lipids have intense biological activity; they include some
of the vitamins and hormones.
Although lipids are a distinct class of
biomolecules, we shall see that they often occur combined, either covalently or
through weak bonds, with members of other classes of biomolecules to yield
hybrid molecules such as glycolipids,
which contain both carbohydrate and lipid groups, "and lipoproteins, which contain both lipids
and proteins. In such biomolecules the distinctive chemical and physical properties
of their components are blended to fill specialized biological functions.
Lipids have been classified in
several different ways. The most satisfactory classification is based on their
backbone structures:
1.
Simple
lipids:
1) acylglycerols;
2) steroids;
3) waxes.
2. Complex lipids:
1)
phospholipids
a)
glycerophospholipids;
b) sphingophospholipids.
2) glycolipids
a) glycosylglycerols;
b) glycosphingolipids.
Lipids usually
contain fatty acids as components. Such lipids are called saponifiable lipids since
they yield soaps (salts of fatty
acids) on alkaline hydrolysis. The other great group of lipids which do not
contain fatty acids and hence are nonsapomfiable.
Let us first consider the structure
and properties of fatty acids, characteristic components of all the complex
lipids.
Fatty acids and glycerides
Fatty acids fill two major roles in the
body:
·
1. as the components of more complex membrane lipids.
·
2. as the major components of stored fat in the form of
triacylglycerols.
Fatty acids are long-chain hydrocarbon
molecules containing a carboxylic acid moiety at one end. The numbering of
carbons in fatty acids begins with the carbon of the carboxylate group. At
physiological pH, the carboxyl group is readily ionized, rendering a negative
charge onto fatty acids in bodily fluids.
Fatty acids that
contain no carbon-carbon double bonds are termed saturated fatty acids; those that
contain double bonds are unsaturated fatty acids. The numeric designations used
for fatty acids come from the number of carbon atoms, followed by the number of
sites of unsaturation (eg, palmitic acid is a 16-carbon fatty acid with no
unsaturation and is designated by 16:0). The site of unsaturation in a fatty
acid is indicated by the symbol and the number of the first carbon of the double bond (e.g. palmitoleic
acid is a 16-carbon fatty acid with one site of unsaturation between carbons 9
and 10, and is designated by 16:19).
Saturated fatty acids of less than eight
carbon atoms are liquid at physiological temperature, whereas those containing
more than ten are solid. The presence of double bonds in fatty acids significantly
lowers the melting point relative to a saturated fatty acid.
The majority of body fatty acids are acquired in the
diet. However, the lipid biosynthetic capacity of the body (fatty acid synthase
and other fatty acid modifying enzymes) can supply the body with all the
various fatty acid structures needed. Two key
exceptions to this are the highly unsaturated fatty acids know as linoleic acid
and linolenic acid, containing unsaturation sites beyond carbons 9 and 10.
These two fatty acids cannot be synthesized from precursors in the body, and
are thus considered the essential fatty
acids; essential in the sense that they must be provided in the diet. Since
plants are capable of synthesizing linoleic and linolenic acid humans can
aquire these fats by consuming a variety of plants or else by eating the meat
of animals that have consumed these plant fats.
Chemically, fatty acids
can be described as long-chain monocarboxylic acids and have a general
structure of CH3(CH2)nCOOH. The length of the
chain usually ranges from 12 to 24, always with an even number of carbons. When
the carbon chain contains no double bonds, it is a saturated chain. If it contains
one or more such bonds, it is unsaturated. The presence of double bonds
generally reduces the melting point of fatty acids. Furthermore, unsaturated
fatty acids can occur either in cis or trans geometric isomers. In naturally occurring fatty acids, the
double bonds are in the cis-configuration.
Glycerides are lipids possessing a glycerol (propan-1, 2, 3-triol) core structure with one or more fatty acyl
groups, which are fatty acid-derived chains attached to the glycerol backbone
by ester linkages. Glycerides with three acyl
groups (triglycerides or neutral fats) are the main storage
form of fat in animals and plants.
An important type of glyceride-based molecule found in
biological membranes, such as the cell's plasma membrane and the intracellular membranes of organelles, are the phosphoglycerides or glycerophospholipids. These are phospholipids that contain a glycerol core linked to
two fatty acid-derived "tails" by ester or, more rarely, ether linkages and to one "head"
group by a phosphate ester linkage. The head groups of the
phospholipids found in biological membranes are phosphatidylcholine (also known as
PC, and lecithin), phosphatidylethanolamine (PE),
phosphatidylserine and phosphatidylinositol (PI). These phospholipids are subject to
a variety of functions in the cell: for instance, the lipophilic and polar ends
can be released from specific phospholipids through enzyme-catalysed hydrolysis
to generate secondary messengers involved in signal transduction. In the case of phosphatidylinositol, the head group can be enzymatically
modified by the addition of one, two or three phosphate groups, this
constituting another mechanism of cell signalling. While phospholipids are the major
component of biological membranes, other non-glyceride lipid components like sphingolipids and sterols (such as cholesterol in animal cell membranes) are also found
in biological membranes.
A biological membrane is a form of lipid
bilayer, as is a liposome. Formation of lipid bilayers is an
energetically-favoured process when the glycerophospholipids described above
are in an aqueous environment. In an aqueous system, the polar heads of lipids
orientate towards the polar, aqueous environment, while the hydrophobic tails
minimise their contact with water. The lipophilic tails of lipids (U) tend to
cluster together, forming a lipid bilayer (1) or a micelle (2). Other aggregations are also observed
and form part of the polymorphism of amphiphile (lipid) behaviour. The polar heads (P) face
the aqueous environment, curving away from the water. Phase behaviour is a complicated area within biophysics
and is the subject of current academic research.
Micelles and bilayers form in the polar
medium by a process known as the lipophilic effect. When dissolving a lipophilic or amphiphilic substance in a polar
environment, the polar molecules (i.e. water in an aqueous solution) become
more ordered around the dissolved lipophilic substance, since the polar
molecules cannot form hydrogen bonds to the lipophilic
areas of the amiphphile. So, in an aqueous
environment the water molecules form an ordered "clathrate" cage around the dissolved
lipophilic molecule.
The self-organisation depends on the concentration of
the lipid present in solution. Below the critical micelle concentration, the lipids form a single layer on the
liquid surface and are (sparingly) dispersed in the solution. At the first
critical micelle concentration (CMC-I), the lipids organise in spherical
micelles, at given points above this concentration, other phases are observed
(see lipid polymorphism).
Self-organization of phospholipids. A lipid bilayer is shown on the left and a micelle on the right.
http://www.youtube.com/watch?v=CLaAPl-_rRM&NR=1
Although fatty acids occur in very large amounts as
building-block components of the saponifiable lipids, only traces occur in free
(unesterified) form in cells and tissues. Well over 100 different kinds of
fatty acids have been isolated from various lipids of animals, plants, and
microorganisms. All possess a long hydrocarbon chain and a terminal carboxyl
group. The hydrocarbon chain may be saturated, as in palmitic acid, or it may have one or more double bonds, as in oleic acid; a few fatty acids contain
triple bonds. Fatty acids differ from each other
primarily in chain length and in the number and position of their unsaturated
bonds. They are often symbolized by a shorthand notation that designates the
length of the carbon chain and the number, position, and configuration of the
double bonds. Thus palmitic acid (16 carbons, saturated) is symbolized 16:0
and oleic acid [18 carbons and one double bond (cis) at carbons 9 and 10] is
symbolized 18:1. It is understood that the double bonds are cis (see below)
unless indicated otherwise.
Some
generalizations can be made on the different fatty acids of higher plants and animals.
The most abundant have an even number of carbon atoms with chains between 14
and 22 carbon atoms long, but those with 16 or 18 carbons predominate. The
most common among the saturated fatty acids are palmitic acid (Cis) and stearic
acid (Cis) and among the unsaturated fatty acids oleic acid (Cis). Unsaturated
fatty acids predominate over the saturated ones, particularly in higher
plants and in
animals living at low temperatures. Unsaturated fatty acids have lower melting points
than saturated fatty acids of the same chain length. In most monounsaturated
(monoenoic) fatty acids of higher organisms there is a double bond between
carbon atoms 9 and
There are two kinds of fats,
saturated and unsaturated. Unsaturated fats have at least one
double bond in one of the fatty acids. A double bond happens when two electrons
are shared or exchanged in a bond. They are much stronger than single bonds. Saturated
fats have no double bonds.
Fats have a lot of energy stored up in their molecular bonds. That's why the
human body stores fat as an energy source. When it needs extra fuel, your body
breaks down the fat and uses the energy. Where one molecule of sugar only gives
a small amount of energy, a fat molecule gives off many times more.
Symbol |
Structure
|
Systemic name |
Common name |
Saturated fatty acid
|
|||
С12:0 |
СН3(СН2)10СООН |
n-Dodecanoic |
Lauric |
С14:0 |
СН3(СН2)12СООН |
n-Tetradecanoic |
Myristic |
С16:0 |
СН3(СН2)14СООН |
n-Hexadecanoic |
Palmitic |
С18:0 |
СН3(СН2)16СООН |
n-Octadecanoic |
Stearic |
С20:0 |
СН3(СН2)18СООН |
n-Eicosanoic |
Arachidic |
С22:0 |
СН3(СН2)20СООН |
n-Docosanoic |
Begenic |
С24:0 |
СН3(СН2)22СООН |
n-Tetracosanoic |
Lignoceric |
Unsaturated monoenic fatty acid
|
|||
С16:1 |
СН3(СН2)5СН=СН(СН2)7СООН |
|
Palmitooleic |
С18:1 |
СН3(СН2)7СН=СН(СН2)7СООН |
|
Oleic |
Unsaturated polienic fatty acid
|
|||
С18:2 |
СН3(СН2)4(СН=СНСН2)2(СН2)6СООН |
|
Linoleic |
С18:3 |
СН3СН2(СН=СНСН2)3(СН2)6СООН |
|
Linolenic |
С20:4 |
СН3(СН2)4(СН=СНСН2)4(СН2)2СООН |
|
Arachidonic |
All
Lipids are hydrophobic: that’s the one
property they have in common. This group of molecules includes fats and oils,
waxes, phospholipids, steroids (like cholesterol), and some other related
compounds.
Structure
of Fatty Acids
Fats and oils
are made from two kinds of molecules: glycerol
(a type of alcohol with a hydroxyl group on each of its three carbons) and
three fatty acids joined by
dehydration synthesis. Since there are three fatty acids attached, these are
known as triglycerides. “Bread” and pastries
from a “bread factory” often contain mono- and diglycerides as “dough
conditioners.” Can you figure
out what these molecules would look like? The main distinction between fats and
oils is whether they’re solid or liquid at room temperature, and this, as we’ll
soon see, is based on differences in the structures of the fatty acids they
contain
Essential
fatty acids
When weanling or immature rats are placed
on a fat-free diet, they grow poorly, develop a scaly skin, lose hair, and ultimately
die with many pathological signs. When linoleic
acid is present in the diet, these conditions do not develop. Linolenic acid and arachidonic acid also
prevent these symptoms. Saturated and monounsaturated fatty acids are inactive.
It has been concluded that mammals can synthesize saturated and monounsaturated
fatty acids from other precursors but are unable to make linoleic and linolenic
acids. Fatty acids required in the diet of mammals are called essential fatty acids. The most abundant
essential fatty acid in mammals is linoleic
acid, which makes up from 10 to 20 percent of the total fatty acids of their
triacylglycerols and phosphoglycerides. Linoleic
and linolenic acids cannot be
synthesized by mammals but must be obtained from plant sources, in which they
are very abundant. Linoleic acid is a necessary precursor in mammals for the
biosynthesis of arachidonic acid,
which is not found in plants.
The terms saturated, mono-unsaturated,
and poly-unsaturated refer to the
number of hydrogens attached to the hydrocarbon tails of the fatty acids as
compared to the number of double bonds between carbon atoms in the tail. Fats,
which are mostly from animal sources, have all single bonds between the carbons
in their fatty acid tails, thus all the carbons are also bonded to the maximum
number of hydrogens possible. Since the fatty acids in these triglycerides
contain the maximum possible amouunt of hydrogens, these would be called saturated fats. The hydrocarbon chains
in these fatty acids are, thus, fairly straight and can pack closely together,
making these fats solid at room temperature. Oils, mostly from plant sources,
have some double bonds between some of the carbons in the hydrocarbon tail,
causing bends or “kinks” in the shape of the molecules. Because some of the
carbons share double bonds, they’re not bonded to as many hydrogens as they
could if they weren’t double bonded to each other. Therefore these oils are called
unsaturated fats. Because of the
kinks in the hydrocarbon tails, unsaturated fats can’t pack as closely
together, making them liquid at room temperature.
Many people have heard that the
unsaturated fats are “healthier” than the saturated ones. Hydrogenated vegetable oil (as in shortening and commercial peanut
butters where a solid consistency is sought) started out as “good” unsaturated
oil. However, this commercial product has had all the double bonds artificially
broken and hydrogens artificially added (in a chemistry lab-type setting) to
turn it into saturated fat that bears no resemblance to the original oil from
which it came (so it will be solid at room temperature).
Although the specific functions of
essential fatty acids in mammals were a mystery for many years, one function
has been discovered. Essential fatty acids are necessary precursors in the
biosynthesis of a group of fatty acid derivatives called prostaglandins, hormonelike compounds which in trace amounts have
profound effects on a number of important physiological activities.
Physical and chemical properties of fatty acids
Saturated and unsaturated
fatty acids have quite different conformations. In saturated fatty acids, the
hydrocarbon tails are flexible and can exist in a very large number of conformations
because each single bond in the backbone has complete freedom of rotation.
Unsaturated fatty acids, on the other hand, show one or more rigid kinks contributed
by the nonrotating double bond(s).
Unsaturated fatty acids
undergo addition reactions at their double bonds. Quantitative titration with
halogens, e.g., iodine or bromine, can yield information on the relative
number of double bonds in a given sample of fatty acids or lipid.
Triacylglycerols (Triglycerides)
Fat is also known as a
triglyceride. It is made up of a molecule known as glycerol
that is connected to one, two, or three fatty acids. Glycerol is the basis of
all fats and is made up of a three-carbon chain. It connects the fatty
acids together. A fatty acid is a long chain of carbon atoms connected
to each other.
Fatty acid esters of the
alcohol glycerol are called acylglycerols
or glycerides; they are
sometimes referred to as "neutral
fats," a term that has become archaic. When all three hydroxyl groups
of glycerol are esterified with fatty acids, the structure is called a triacylglycerol:
Although the name
"triglyceride" has been traditionally used to designate these
compounds, an international nomenclature commission has recommended that this
chemically inaccurate term no longer be used. Triacylglycerols are the most
abundant family of lipids and the major components of depot or storage lipids
in plant and animal cells. Triacylglycerols that are solid at room temperature
are often referred to as "fats" and those which are liquid as
"oils." Diacylgiycerols
(also called diglycerides) and monoacylgiycerols (or monoglycerides) are
also found in nature, but in much smaller amounts.
Triacylglycerols occur in many
different types, according to the identity and position of the three fatty acid
components esterified to glycerol. Those with a single kind of fatty acid in
all three positions, called simple triacylglycerols, are named after the fatty
acids they contain. Examples are tristearoylglycerol,
tripalmitoylglycerol, and trioleoylglycerol; the trivial
and more commonly used names are tristearin,
tripalmitin, and trioiein, respectively. Mixed triacylglycerols
contain two or more different fatty acids. The naming of mixed triacylglycerols
can be illustrated by the example of 1-palmitoyldi-stearoylglycerol
(trivial name, 1-palmitodistearin).
Most natural fats are extremely complex mixtures of simple and mixed
triacylglycerols.
Properties of
triacylglycerols
The melting point of triacylglycerols
is determined by their fatty acid components. In general, the melting point increases
with the number and length of the saturated fatty acid components. For example,
tripalmitin and tristearin are solids at body temperature, whereas triolein and
trilinolein are liquids. All triacylglycerols are insoluble in water and do not
tend by themselves to form highly dispersed micelles. However, diacylglycerols
and monoacylglycerols have appreciable polarity because of their free hydroxyl
groups and thus can form micelles. Diacyl- and monoacylglycerols find wide use
in the food industry in the production of more homogeneous and more easily
processed foods; they are completely digestible and utilized biologically.
Acylglycerols are soluble in ether, chloroform, benzene, and hot ethanol. Their
specific gravity is lower than that of water. Acylglycerols undergo hydrolysis
when boiled with acids or bases or by the action of lipases, e.g., those
present in pancreatic juice. Hydrolysis with alkali, called saponification,
yields a mixture of soaps and glycerol.
Steroids occur in
animals in something called hormones. The basis of a steroid
molecule is a four-ring structure, one with five carbons and three with six
carbons in the rings. You may have heard of steroids in the news. Many body
builders and athletes use anabolic steroids to build muscle mass. The steroids
make their body want to add more muscle than they normally would be able to.
The body builders wind up stronger and bulkier (but not faster).
Never take drugs to enhance your body. Those body builders are actually hurting
their bodies. They can't see it because it is slowly destroying their internal
organs and not the muscles.
When they get
older, they can have kidney and liver problems. Some even die. The important class of lipids called steroids are actually metabolic
derivatives of terpenes, but they are customarily treated as a separate group.
Steroids may be recognized by their tetracyclic skeleton, consisting of three
fused six-membered and one five-membered ring, as shown in the diagram to the
right. The four rings are designated A, B, C & D as noted, and the peculiar
numbering of the ring carbon atoms (shown in red) is the result of an earlier
misassignment of the structure. The substituents designated by R are often
alkyl groups, but may also have functionality. The R group at the A:B ring
fusion is most commonly methyl or hydrogen, that at the C:D fusion is usually
methyl. The substituent at C-17 varies considerably, and is usually larger than
methyl if it is not a functional group. The most common locations of functional
groups are C-3, C-4, C-7, C-11, C-12 & C-17. Ring A is sometimes aromatic.
Since a number of tetracyclic triterpenes also have this tetracyclic structure,
it cannot be considered a unique identifier.
Steroids are widely distributed in animals, where they are associated
with a number of physiological processes. Examples of some important steroids
are shown in the following diagram. Different kinds of steroids will be
displayed by clicking the "Toggle Structures" button under the
diagram. Norethindrone is a synthetic steroid, all the other examples occur
naturally. A common strategy in pharmaceutical chemistry is to take a natural
compound, having certain desired biological properties together with undesired
side effects, and to modify its structure to enhance the desired
characteristics and diminish the undesired. This is sometimes accomplished by
trial and error.
The generic steroid structure drawn above has seven chiral stereocenters
(carbons 5, 8, 9, 10, 13, 14 & 17), which means that it may have as many as
128 stereoisomers. With the exception of C-5, natural steroids generally have a
single common configuration. This is shown in the last of the toggled displays,
along with the preferred conformations of the rings.
Chemical studies of the steroids were very important to our present
understanding of the configurations and conformations of six-membered rings. Substituent
groups at different sites on the tetracyclic skeleton will have axial or
equatorial orientations that are fixed because of the rigid structure of the
trans-fused rings. This fixed orientation influences chemical reactivity,
largely due to the greater steric hindrance of axial groups versus their
equatorial isomers. Thus an equatorial hydroxyl group is esterified more
rapidly than its axial isomer.
Steroids are complex ethers of cyclic spirits sterols and fatty acids. Sterols are
derivatives of the saturated tetracylic hydrocarbon
cyclopentanoperhydrophenanthrene:
Cyclopentanoperhydrophenanthrene Cholesterol
The general structure of cholesterol
consists of two six-membered rings side-by-side and sharing one side in common,
a third six-membered ring off the top corner of the right ring, and a
five-membered ring attached to the right side of that.
The central core of this molecule, consisting of four fused rings, is
shared by all steroids, including
estrogen (estradiol), progesterone, corticosteroids such as cortisol
(cortisone), aldosterone, testosterone, and Vitamin D. In the various types of
steroids, various other groups/molecules are attached around the edges. Know
how to draw the four rings that make up the central structure.
Cholesterol is not a “bad guy!” Our bodies make about
Many people have hear the claims that egg yolk contains
too much cholesterol, thus should not be eaten. An interesting study was done
at
A great many different steroids, each
with a distinctive function or activity, have been isolated from natural
sources. Steroids differ in the number and position of double bonds, in the
type, location, and number of substituent functional groups, in the
configuration of the bonds between the substituent groups and the nucleus, and
in the configuration of the rings in relation to each other.
Cholesterol is the most
abundant steroid in animal tissues. Cholesterol and lanosterol are members of a
large subgroup of steroids called the sterols. They are steroid alcohols
containing a hydroxyl group at carbon 3 of ring A and a branched aliphatic
chain of eight or more carbon atoms at carbon 17. They occur either as free
alcohols or as long-chain fatty acid esters of the hydroxyl group at carbon 3;
all are solids at room temperature. Cholesterol melts at
Cholesterol is the precursor of many
other steroids in animal tissues, including the bile acids, detergentlike compounds that aid in
emulsification and absorption of lipids in the intestine; the androgens, or male sex hormones; the estrogens, or female sex
hormones; the progestational hormone progesterone; and the adrenocortical hormones. Among the most important steroids are a
group of compounds having vitamin D activity.
Waxes
Waxes are water-insoluble,
solid esters of higher fatty acids with long-chain monohydroxylic fatty
alcohols or with sterols. They are soft and pliable when warm but hard when
cold. Waxes are found as protective coatings on skin, fur, and feathers, on
leaves and fruits of higher plants, and on the exoskeleton of many insects. The
major components of beeswax are palmitic acid esters of long-chain fatty
alcohols with 26 to 34 carbon atoms. Lanolin,
or wool fat, is a mixture of fatty acid esters of the sterols lanosterol and
agnosterol.
Waxes are used to coat and
protect things in nature. Bees make wax. Your ears make wax. Plant leaves even
have wax on the outside of their leaves. It can be used for structures such as
the bees' honeycombs. Waxes can also be used for protection. Plants use wax to
stop evaporation of
water from their leaves.
Prostaglandins
Thromboxanes & Leukotrienes
The members of this group of structurally
related natural hormones have an extraordinary range of biological effects. They
can lower gastric secretions, stimulate uterine contractions, lower blood
pressure, influence blood clotting and induce asthma-like allergic responses.
Because their genesis in body tissues is tied to the metabolism of the
essential fatty acid arachadonic acid (5,8,11,14-eicosatetraenoic acid) they
are classified as eicosanoids. Many
properties of the common drug asprin result from its effect on the cascade of
reactions associated with these hormones.
The metabolic pathways by which
arachidonic acid is converted to the various eicosanoids are complex and will
not be discussed here. A rough outline of some of the transformations that take
place is provided below. It is helpful to view arachadonic acid in the coiled
conformation shown in the shaded box.
http://www.youtube.com/watch?v=PoolWjqoyO0
Glycerophospholipids
(phosphoglycerides)
The basic structure of phospolipids is very similar to that of
the triacylglycerides except that C-3 (sn3)of
the glycerol backbone is esterified to phosphoric acid. The building block of
the phospholipids is phosphatidic acid which results when the X substitution in
the basic structure shown in the Figure below is a hydrogen atom. Substitutions
include ethanolamine (phosphatidylethanolamine), choline (phosphatidylcholine,
also called lecithins), serine (phosphatidylserine), glycerol
(phosphatidylglycerol), myo-inositol (phosphatidylinositol, these compounds can have a variety in the numbers of inositol alcohols that are phosphorylated generating polyphosphatidylinositols), and phosphatidylglycerol.
Phosphoglycerides are characteristic
major components of cell membranes; only very small amounts of
phosphoglycerides occur elsewhere in cells.
Phospholipids are made from glycerol,
two fatty acids, and (in place of the third fatty acid) a phosphate
group
with some other molecule attached to its other end. The hydrocarbon tails of
the fatty acids are still hydrophobic, but the phosphate group end of the
molecule is hydrophilic because of the oxygens with all of their pairs of
unshared electrons. This means that phospholipids are soluble in both water and
oil.
|
An emulsifying
agent is a substance which is soluble in both oil and water, thus enabling
the two to mix. A “famous” phospholipid is lecithin which is found in egg yolk and soybeans. Egg yolk is
mostly water but has a lot of lipids, especially cholesterol, which are needed
by the developing chick. Lecithin is used to emulsify the lipids and hold them in the water as an emulsion. Lecithin is the basis of the
classic emulsion known as mayonnaise.
http://www.youtube.com/watch?v=7k2KAfRsZ4Q&feature=related
Our cell
membranes are made mostly of phospholipids arranged in a double layer with
the tails from both layers “inside” (facing toward each other) and the heads
facing “out” (toward the watery environment) on both surfaces.
In phosphoglycerides one of
the primary hydroxyl groups of glycerol is esterified to phosphoric acid; the
other hydroxyl groups are esterified to fatty acids. The parent compound of
the series is thus the phosphoric ester of glycerol.
Because
phosphoglycerides possess a polar head in addition to their nonpolar
hydrocarbon tails, they are called amphipathic
or polar lipids. The different types
of phosphoglycerides differ in the size, shape, and electric charge of their
polar head groups.
The parent compound of the
phosphoglycerides is phosphatidic acid,
which contains no polar alcohol head group. It occurs in only very small
amounts in cells, but it is an important intermediate in the biosynthesis of
the phosphoglycerides.
posphatidic acid
The most abundant phosphoglycerides
in higher plants and animals are phosphatidylethanoamme
and phosphatidylchohne, which contain
as head groups the amino alcohols ethanoiamine
and choline, respectively.
(The new names recommended for these phosphoglycerides are ethanolamine
phosphoglyceride and choline phosphoglyceride, but they have not yet
gained wide use. The old trivial names are cephalin
and lecithin, respectively.) These
two phosphoglycerides are major components of most animal cell membranes.
In phosphqtidylserine, the hydroxyl
group of the amino acid L-serine is esterified to the phosphoric acid.
Closely related to
phosphatidylglycerol is the more complex lipid cardiolipin, also called diphosphatidylglycerol,
which consists of a molecule of phosphatidylglycerol in which the 3'-hydroxyl
group of the second glycerol moiety is esterified to the phosphate group of a
molecule of phosphatidic acid. The backbone of cardiolipin thus consists of three molecules of glycerol joined by
two phosphodiester bridges; the two hydroxyl groups of both external glycerol
molecules are esterified with fatty acids. Cardiolipin
is present in large amounts in the inner membrane of mitochondria; it was first
isolated from heart muscle, in which mitochondria are abundant.
http://www.youtube.com/watch?v=kOTRNFZHmTI&feature=related
Lipid
Soluble Vitamins
The essential dietary
substances called vitamins are
commonly classified as "water soluble" or "fat soluble".
Water soluble vitamins, such as vitamin C, are rapidly eliminated from the body
and their dietary levels need to be relatively high. The recommended daily
allotment (RDA) of vitamin C is 100 mg, and amounts as large as 2 to
Vitamin
A 800 μg ( upper limit ca. 3000 μg)
Vitamin D 5 to 10 μg ( upper limit ca. 2000 μg)
Vitamin E 15 mg ( upper limit ca.
Vitamin K 110 μg ( upper limit not specified)
From this data it is clear that vitamins A and D, while essential to
good health in proper amounts, can be very toxic. Vitamin D, for example, is
used as a rat poison, and in equal weight is more than 100 times as poisonous
as sodium cyanide. From the structures shown here, it should be clear that
these compounds have more than a solubility connection with lipids. Vitamins A
is a terpene, and vitamins E and K have long terpene chains attached to an
aromatic moiety. The structure of vitamin D can be described as a steroid in
which ring B is cut open and the remaining three rings remain unchanged. The
precursors of vitamins A and D have been identified as the tetraterpene
beta-carotene and the steroid ergosterol, respectively.
Phosphoglycerides have variations in the size, shape, polarity, and
electric charge and it plays a significant role in the structure of various
types of cell membranes.
Phosphoglycerides can be hydrolyzed
by specific phospholipases, which
have become important tools in the determination of phosphoglyceride structure.
Phospholipase A1 specifically removes the fatty acid from the 1 position and
phospholipase A2 from the 2 position. Removal of one fatty acid molecule from
a phosphoglyceride yields a lysophosphoglyceride,
e.g., lysophosphatidyl-ethanolamine. Lysophosphoglycerides are
intermediates in phosphoglyceride metabolism but are found in cells or tissues
in only very small amounts; in high concentrations they are toxic and injurious
to membranes. Phospholipase B can bring about successive removal of the two
fatty acids of phosphoglycerides. Phospholipase C hydrolyzes the bond between
phosphoric acid and glycerol, while phospholipase D removes the polar head
group to leave a phosphatidic acid.
Sphingolipids are composed of a backbone of sphingosine which is derived
itself from glycerol. Sphingosine is N-acetylated by a variety of fatty acids
generating a family of molecules referred to as ceramides. Sphingolipids
predominate in the myelin sheath of nerve fibers. Sphingomyelin is an abundant
sphingolipid generated by transfer of the phosphocholine moiety of
phosphatidylcholine to a ceramide, thus sphingomyelin is a unique form of a
phospholipid.
The other
major class of sphingolipids (besides the sphingomyelins) are the
glycosphingolipids generated by substitution of carbohydrates to the sn1 carbon of the glycerol backbone of a
ceramide. There are 4 major classes of
glycosphingolipids:
n
Cerebrosides: contain a single moiety, principally galactose.
n
Sulfatides: sulfuric acid esters of galactocerebrosides.
n
Globosides: contain 2 or more sugars.
n
Gangliosides: similar to globosides except also contain sialic acid.
Sphingolipids
Glycosyldiqcylglycerols contain a sugar in glycosidic linkage with the unesterified 3-hydroxyl
group of diacylglycerols. A common example is galactosyldiacylglycerol, found in higher
plants and also in neural tissue of vertebrates.
Glycosphingolipids
Neutral glycosphingolipids
This class of glycolipids contains
one or more neutral sugar residues as their polar head groups and thus has no
electric charge; they are called neutral glycosphingolipids. The simplest of
these are the cerebrosides, which
contain as their polar head group a monosaccharide bound in beta-glycosidic
linkage to the hydroxyl group of ceramide.
The cerebrosides of the brain and nervous system contain D-galactose and are
therefore called galactocerebrosides.
Cerebrosides are also present in much smaller amounts in nonneural tissues of
animals, where, because they usually contain D-glucose instead of D-galactose,
they are called glucocerebrosides.
Sulfate esters of
galactocerebrosides (at the 3 position of the D-galactose) are also present in
brain tissue; they are called sulfotides.
The neutral glycosphingolipids are
important cell-surface components in animal tissues. Their nonpolar tails
presumably penetrate into the lipid bilayer structure of cell membranes,
whereas the polar heads protrude outward from the surface. Some of the neutral
glycosphingolipids are found on the surface of red blood cells and give them
blood-group specificity.
Acidic
glycosphingolipids (gangliosides)
Gangliosides contain in their oligosaccharide
head groups one or more residues of a sialic acid, which gives the polar head
of the gangliosides a net negative charge at pH 7.0. The sialic acid usually
found in human gangliosides is N-acetylneuraminic
acid. Gangliosides are most abundant in the gray matter of the brain, where
they constitute 6 percent of the total lipids, but small amounts are also found
in nonneural tissues.
Function of glycosphingolipids
Although glycosphingolipids are only
minor constituents of membranes, they appear to be extremely important in a
number of specialized functions. Because gangliosides are especially abundant
in nerve endings, it has been suggested that they function in the transmission
of nerve impulses across synapses. They are also believed to be present at
receptor sites for acetylcholine and other neurotransmitter substances. Some of
the cell-surface glycosphingolipids are concerned not only in blood-group
specificity but also in organ and tissue specificity. These complex lipids are
also involved in tissue immunity and in cell-cell recognition sites fundamental
to the development and structure of tissues. Cancer cells, for example, have
characteristic glycosphingolipids different from those in normal cells.
The lipids discussed up to
this point contain fatty acids as building blocks, which can be released on
alkaline hydrolysis. The simple lipids contain no fatty acids. They occur in
smaller amounts in cells and tissues than the complex lipids, but they include
many substances having profound biological activity—vitamins, hormones, and
other highly specialized fat-soluble biomolecules.
Prostaglandins are a family of
fatty acid derivatives which have a variety of potent biological activities of
a hormonal or regulatory nature. Prostaglandins function as regulators of
metabolism in a number of tissues and in a number of ways.
All the natural prostaglandins
are biologically derived by cyclization of 20-carbon unsaturated fatty acids,
such as arachidonic acid, which is formed from the essential fatty acid
linoleic acid. The prostaglandins differ from each other with respect to their
biological activity, although all show at least some activity in lowering
blood pressure and inducing smooth muscle to contract. Some, like PGE2,
antagonize the action of certain hormones. PGE2 and PGE2a may find clinical use in inducing labor and bringing
about therapeutic abortion.
Digestion of fats
By
far the most common of the diet are the neutral fats, also known as triglycerides, each molecule of which is
composed of a glycerol nucleus and three fatty acids, as illustrated. Neutral
fat is found in food of both animal and and plant origin. In the usual diet are
also small quantities of phospholipids, cholesterol, and cholesterol esters.
Digestion of fats in the intestine. A small amount of short chain triglycerides is
digested in the stomach by gastric
lipase.
Emulsification of fat by bile acids. The first in fat digestion is to break the fat
globules into s sizes so that the water-soluble digestive enzymes act on the
globule surfaces. This process is called emulsification
of the
fat, and it is achieved under
the presence of bile acids. Bile
contain a large quantity of bile salts,
mainly in the form of ionized sodium salts.
The carboxyl and other parts of the
bile salt molecule are highly soluble in water, whereas most of the sterol
portion of the bile is highly soluble in fat. Therefore, the fat-soluble
portion of the bile salt dissolves in the surface layer of the fat globule and
polar portion of the bile salt is soluble in the surrounding fluids. This
effect decreases the interfacial tension of the fat. When the interfacial
tension of a globule is low, globule is broken up into many minute particles.
The total surface area of the particles
in the intestinal contents is inversely proportional to the diameters of the
particles. The lipases are water-soluble compounds and can act on the fat
globules only on their surfaces. Consequently, it can be readily understood how
important detergent function of bile salts is for the digestion of fats.
Digestion of fats by pancreatic
lipase. The most
important enzyme for the digestion of fats is pancreatic lipase in the pancreatic juice. However, the cells of
the small intestine also contain a minute quantity of lipase known as enteric lipase. Both liiese act alike to cause hydrolysis of fat.
Products of fat digestion. Most
of the triglycerides of the diet are split into free fatty acids and
monoglycerides.
Role of bile salts in accelerating fat
digestion — formation of micelles. The
hydrolysis of triglycerides highly reversible process; therefore, accumulation
of monoglycerides and free fatty acids very quickly blocks further digestion.
The bile salts play an important role in
removing the monoglycerides and free fatty acids from the vicinity of the digesting fat globules almost as rapidly as these
end-products of digestion are formed. This occurs in the following way:
bile salts have the propensity to form
micelles, which are small spherical globules
composed of 20 to 40 molecules of bile salt. These develop because each bile salt molecule is composed of a sterol
nucleus, most of which is highly fat-soluble, and a polar group that is highly
water-soluble. The sterol nuclei of
the 20 to 40 bile salt molecules of the micelle aggregate together to form a
small fat globule in the middle of the micelle. This aggregation causes the polar groups to project outward to cover
the surface of the micelle During
triglyceride digestion, as rapidly as the monoglycerides and free fatty acids
are formed they become dissolved in the fatty portion of the micelles, which
immediately reduces these end-products of digestion in the vicinity of the
digesting fat globules. The bile salt
micelles also act as a transport medium to carry the monoglycerides and the
free fatty acids, both of which would otherwise be relatively insoluble, to the
brush borders of the epithelial cells. There
the monoglycerides and free fatty acids are absorbed. On delivery of these substances to the brush border, the bile salts are
again released
back into the chyme to be used
again and again for this "ferrying" process.
Digestion of Cholesterol Esters and Phospholipids. Most of the cholesterol in the diet is in the form of cholesterol esters, which are combinations of free cholesterol and one molecule of fatty acid. And phospholipids also contain fatty acid chains within their molecules. Both the cholesterol esters and the phospholipids are hydrolyzed by lipases in the pancreatic secretion that free the fatty acids — the enzyme cholesterol ester hydrolase to hydrolyze the cholesterol ester and phospholipase A to hydrolyze the phospholipid.
The bile salt
micelles play identically the same role in "ferrying" free
cholesterol as they play in "ferrying" monoglycerides and free fatty
acids. Indeed, this role of the bile
salt micelles is absolutely essential to the absorption of cholesterol because
essentially no cholesterol is absorbed without the presence of bile salts.
On the other hand, as much as 60 per cent
of the triglycerides can be digested and absorbed even in the absence of bile
salts.
Absorption of fats
Monoglycerides and fatty acids -
both of digestive end-products - become dissolved in the lipid portion of the
micelles. Because of the molecular dimension of these micelles, only 2.5
nanometers, and also because of their highly charged, they are soluble in the
chyme. Micelles contact with the
surfaces of the brush border even penetrating into the recesses , agitating
microvilli.
The micelles then diffuse back through the chyme and absorb still more monoglycerides and fatty acids, and similarly transport these also to the epithelial cells. Thus, the bile acids perform a "ferrying" function, which is highly important for fat absorption. In the presence of an abundance of bile acids, approximately 97 per cent of the fat is absorbed; in the absence of bile acids, only 50 to 60 per cent is normally absorbed.
The mechanism for absorption of the monoglycerides and fatty acids through the brush border is based entirely on the fact that both these substances are highly lipid-soluble. Therefore, they become dissolved in the membrane and simply diffuse to the interior of the cell. The undigested triglycerides and the diglycerides are both also highly soluble in the lipid membrane of the epithelial cell. However, only small quantities of these are normally absorbed because the bile acid micelles will not dissolve either triglycerides or diglycerides and therefore will not ferry them to the epithelial membrane.
After entering the epithelial cell, the
fatty acids and monoglycerides are taken up by the smooth endoplasmic
reticulum, and here they are mainly recombined to form new triglycerides. However, a few of the monoglycerides are
further digested into glycerol and fatty acids by an epithelial cell lipase.
Then, the free fatty acids are
reconstituted by the smooth endoplasmic reticulum into triglycerides. Most of the glycerol that is utilized for
this purpose is synthesized de novo from alpha-glycerophosphate, this synthesis
requiring both energy from ATP and a complex of enzymes to catalyze the
reactions. Once formed, the
triglycerides aggregate within the endoplasmic reticulum into globules along with absorbed cholesterol, absorbed
phospholipids, and small amounts of newly synthesized cholesterol and
phospholipids. The phospholipids
arrange themselves in these globules with the fatty portion of the phospholipid
toward the center and the polar portions located on the surface. This provides an electrically charged
surface that makes these globules miscible with the fluids of the cell. In addition, small amounts of lipoprotein,
also synthesized by the endoplasmic reticulum, coat part of the surface of each
globule. In this form the globule
diffuses to the side of the epithelial cell and is excreted by the process of
cellular exocytosis into the space
between the cells; from there it
passes into the lymph in the central lacteal of the villus. These globules are
then called chylomicrons.
Transport of the Chylomicrons in the Lymph. From the sides of the epithelial cells the chylomicrons wend their way
into the central lac-teals of the villi and from here are propelled, along with
the lymph, by the lymphatic pump upward through the thoracic duct to be emptied
into the great veins of the neck. Between
80 and 90 per cent of all fat absorbed from the gut is absorbed in this manner
and is transported to the blood by
way of the thoracic lymph in the form of chylomicrons.
Direct
Absorption of fatty acids into the portal blood. Small quantities of short chain fatty acids, such as those from
butterfat, are absorbed directly into the portal blood rather than being
converted into triglycerides and absorbed into the lymphatics. The cause of this difference between short
and long chain fatty acid absorption is that the shorter chain fatty acids are
more water-soluble and are not reconverted into triglycerides by the
endoplasmic reticulum. This allows
direct diffusion of these fatty acids from the epithelial cells into the
capillary blood of the dlood.
Fatty acids
play an extremely important part as an energy-rich fuel in higher animals and
plants since large amounts can be stored in cells in the form of
triacylglycerols. Triacylglycerols are especially well adapted for this role
because they have a high energy content (about 9 kcal/g) and can be accumulated
in nearly anhydrous form as intracellular fat droplets. In contrast, glycogen
and starch can yield only about 4 kcal/g; moreover, since they are highly
hydrated, they cannot be stored in such
concentrated form. Fatty acids provide up to 40 percent of the total fuel
requirement in man on a normal diet.
http://www.youtube.com/watch?v=3xF_LK9pnL0&feature=related
Mammalian tissues normally contain only
vanishingly small amounts of free fatty acids, which are in fact somewhat
toxic. By the action of hormonally controlled lipases free fatty acids are
formed from triacylglycerols in fat or adipose tissue. The free fatty acids are
then released from the tissue, become tightly bound to serum albumin, and in
this form are carried via the blood to other tissues for oxidation. Fatty acids
delivered in this manner are first enzymatically "activated" in the
cytoplasm and then enter the mitochondria for oxidation.
Long-chain fatty acids are oxidized
to CO2 and H2O in nearly all tissues of vertebrates
except the brain. Some tissues, such as heart muscle, obtain most of their
energy from the oxidation of fatty acids. The mobilization, distribution, and
oxidation of fatty acids are integrated with the utilization of carbohydrate
fuels; both are under complex endocrine regulation.
The pathway of fatty acid oxidation.
Knoop
postulated that fatty acids are oxidized by b-oxidation,
i.e., oxidation at the b carbon to
yield a b-keto acid, which was assumed to
undergo cleavage to form acetic acid and a fatty acid shorter by two carbon
atoms.
Outline of the fatty acid oxidation
cycle.
Before
oxidation, long-chain fatty acids from the cytosol must undergo a rather complex
enzymatic activation, followed by transport across the mitochondrial membranes
into the major compartment. There the fatty acyl group is transferred to
intramitochondrial coenzyme A, yielding a fatty acyl-CoA thioester. The
subsequent oxidation of the fatty acyl-CoA takes place entirely in the
mitochondrial matrix. The fatty
acyl-CoA is dehydrogenated by removal of a pair of hydrogen atoms from the a and b carbon atoms (atoms 2 and 3) to yield the a,b-unsaturated acyl-CoA. This is then enzymatically
hydrated to form a b-hydroxyacyl-CoA, which in turn is dehydrogenated in
the next step to yield the b-ketoacyl-CoA. It then undergoes enzymatic cleavage by
reaction with a second molecule of CoA. One product is acetyl-CoA, derived
from carbon atoms 1 and 2 of the original fatty acid chain. The other product,
a long-chain saturated fatty acyl-CoA having two fewer carbon atoms than the
original fatty acid, now becomes the substrate for another round of reactions,
beginning at the first dehydrogenation step and ending with the removal of a
second two-carbon fragment as acetyl-CoA. At each passage through this spiral
the fatty acid chain loses a two-carbon fragment as acetyl-CoA. The 16-carbon
palmitic acid thus undergoes a total of seven such cycles, to yield altogether
8 molecules of acetyl-CoA and 14 pairs of hydrogen atoms. The palmitate must be
primed or activated only once, since at the end of each round the shortened
fatty acid appears as its CoA thioester.
The hydrogen atoms
removed during the dehydrogenation of the fatty acid enter the respiratory
chain; as electrons pass to molecular oxygen via the cytochrome system,
oxidative phosphorylation of ADP to ATP occurs. The acetyl-CoA formed as
product of the fatty acid oxidation system enters the tricarboxylic acid cycle.
Activation and entry of fatty acids into mitochondria.
There are three stages in the entry of fatty acids into mitochondria
from the extramitochondrial cytoplasm: (1) the enzymatic ATP-driven
esterification of the free fatty acid with extramitochondrial CoA to yield
fatty acyl-CoA, a step often referred to as the activation of the fatty acid,
(2) the transfer of the acyl group from the fatty acyl-CoA to the carrier
molecule carnitine, followed by the transport of the acyl carnitine across the
inner membrane, and (3) the transfer of the acyl group from fatty acyl
carnitine to intramitochondrial CoA.
Activation of fatty acids.
At least three different enzymes
catalyze formation of acyl-CoA thioesters, each being specific for a given
range of fatty acid chain length. These enzymes are called acyl-CoA
synthetases. Acetyl-CoA synthetase activates acetic, propionic, and acrylic
acids, medium-chain acyl-CoA synthetase activates fatty acids with 4 to
12 carbon atoms, and long-chain acyI-CoA synthetase activates fatty acids with
12 to 22 or more carbon atoms. The last two enzymes activate both saturated
and unsaturated fatty acids. Otherwise the properties and mechanisms of all
three synthetases, which have been isolated in highly purified form, are nearly
identical. The overall reaction catalyzed by the ATP-linked acyl-CoA
synthetases is:
RCOOH + ATP + CoA–SH Û
RCO—S—CoA + AMP + PP
Fatty
acids
acyl-CoA
In this
reaction a thioester linkage is formed between the fatty acid carboxyl group
and the thiol group of CoA; the ATP undergoes pyrophosphate cleavage to yield
AMP and inorganic pyrophosphate.
The acyl-CoA synthetases
are found in the outer mitochondrial membrane and in the endoplasmic reticulum.
Transfer
to carnitine.
Long-chain saturated fatty acids have
only a limited ability to cross the inner membrane as CoA
thioesters, but their entry is greatly stimulated by carnitine.
The stimulation of fatty acid
oxidation by carnitine is due to the action of an enzyme carnitine acyltransferase, which catalyzes transfer of the fatty
acyl group from its thioester linkage with CoA to an oxygen-ester linkage with
the hydroxyl group of carnitine. The acyl carnitine ester so formed then passes
through the inner membrane into the matrix, presumably via a specific
transport system.
Carnitine Acyl-CoA
Acyl-carnitine
Transfer to
intramitochondrial CoA.
In the last stage of the entry process the acyl group
is transferred from carnitine to intramitochondrial CoA by the action of a
second type of carnitine acyltransferase
located on the inner surface of the inner membrane:
Acyl carnitine + CoA Û acyl-CoA + carnitine
This complex entry mechanism,
often called the fatty acid shuttle, has the effect of keeping the
extramitochondrial and intramitochondrial pools of CoA and of fatty acids
separated. The intramitochondrial fatty acyl-CoA now becomes the substrate of
the fatty acid oxidation system, which is situated in the inner matrix
compartment.
The first dehydrogenation step in
fatty acid oxidation.
Following
the formation of intramitochondrial acyl-CoA, all subsequent reactions of the
fatty acid oxidation cycle take place in the inner compartment. In the first
step the fatty acyl-CoA thioester undergoes enzymatic dehydrogenation by acyl-CoA dehydrogenase at the a and b carbon atoms (carbons 2 and 3) to form enoyl-CoA as product. The double
bond formed in this reaction has the trans geometrical configuration. Recall,
however, that the double bonds of the unsaturated fatty acids of natural fats
nearly always have the cis configuration.
There are four different
acyl-CoA dehydrogenases, each specific for a given range of fatty acid chain
lengths. All contain tightly bound flavin adenine dinucleotide (FAD) as
prosthetic groups. The FAD becomes reduced at the expense of the substrate, a
process that probably occurs through distinct one-electron steps.
The FADH2 of the
reduced acyl-CoA dehydrogenase cannot react directly with oxygen but donates
its electrons to the respiratory chain
via a second flavoprotein, electron-transferring flavoprotein, which in
turn passes the electrons to some carrier of the respiratory chain.
The double bond of the enoyl-CoA ester is then hydrated to form 3-hydroxyacyl-CoA by the enzyme enoyl-CoA hydratase.
The addition of water across the trans double bond is stereo-specific
and results in the formation of the L-stereoisomer of the 3-hydroxyacyl-CoA.
The
second dehydrogenation step.
In the next
step of the fatty acid oxidation cycle, the 3-hydroxyacyl-CoA is dehydrogenated
to form 3-ketoacyl-CoA) by 3-hydroxyacyl-CoA dehydrogenase. NAD+
is the specific electron acceptor. The reaction is:
This enzyme
is relatively nonspecific with respect to the length of the fatty acid chain
but is absolutely specific for the l stereoisomer.
The NADH formed in the reaction donates its electron equivalents to the NADH
dehydrogenase of the mitochondrial respiratory chain.
The cleavage step.
In the last step of the fatty
acid oxidation cycle, which is catalyzed by acetyl-CoA
acetyltransferase, more commonly
known as thiolase, the 3-ketoacyl-CoA
undergoes cleavage by interaction with a molecule of free CoA to yield the
carboxyl-terminal two-carbon fragment of the fatty acid as acetyl-CoA. The
remaining fatty acid, now shorter by two carbon atoms, appears as its coenzyme
A thioester.
This cleavage reaction, also called a
thiolysis or a thiolytic cleavage, is analogous to hydrolysis. Since the
reaction is highly exergonic, cleavage is favored. There appear to be two
(perhaps three) forms of the enzyme, each specific for different fatty acid
chain lengths.
The balance sheet.
We have described one turn of the
fatty acid oxidation cycle, in which one molecule of acetyl-CoA and two pairs
of hydrogen atoms have been removed from the starting long-chain fatty
acyl-CoA. The overall equation for one turn of the cycle, starting from
palmitoyl-CoA, is
Palmitoyl-CoA + CoA + FAD+ + NAD+ + H2O ®
myristoyl-CoA
+ acetyl-CoA + FADH2 + NADH2
We
can now write the equation for the seven turns of the cycle required to convert
one molecule of palmitoyl-CoA into eight molecules of acetyl-CoA:
Palmitoyl-CoA + 7CoA + 7FAD+ + 7NAD+ + 7H2O
®
8 acetyl-CoA + 7FADH2 + 7NADH2 + 7H+
Each molecule of FADH2 donates
a pair of electron equivalents to the respiratory chain at the level of
coenzyme Q; thus two molecules of ATP are generated during the ensuing electron
transport to oxygen. Similarly, oxidation of each molecule of NADH2
by the respiratory chain results in formation of three molecules of ATP. Hence, a total of five molecules of ATP is
formed by oxidative phosphorylation per molecule of acetyl-CoA cleaved.
The seven turns of the cycle required to
convert one molecule of palmitoyl-CoA rsults in the formation of 5 x 7 = 35
ATP.
The eight molecules of acetyl-CoA formed in the
fatty acid cycle may now enter the tricarboxylic acid cycle. The degradation of
1 molecule of acetyl-CoA in tricarboxylic acid cycle results in the formation
of 12 molecules of ATP. 8 molecules of acetyl-CoA give 96 molecules of ATP.
Thus, the total output of energy in full
cleavage of 1 molecule of palmitoyl-CoA is: 35 + 96 = 131 molecules of ATP.
Since one molecule of ATP is
in effect utilized to form palmitoyl-CoA from palmitate, the net yield of ATP
per molecule of palmitate is 130.
Oxidation of unsaturated fatty acids.
Unsaturated
fatty acids, such as oleic acid, are oxidized by the same general pathway as
saturated fatty acids, but two special problems arise. The double bonds of
naturally occurring unsaturated fatty acids are in the cis configuration,
whereas the unsaturated acyl-CoA intermediates in the oxidation of saturated
fatty acids are trans, as we have seen. Moreover, the double bonds of most
unsaturated fatty acids occur at such positions in the carbon chain that successive
removal of two-carbon fragments from the carboxyl end yields a D3-unsaturated
fatty acyl-CoA rather than the D2 fatty acyl-CoA serving as the normal
intermediate in the fatty acid cycle.
These problems have been resolved
with the discovery of an auxiliary enzyme, enoyl-CoA isomerase, which
catalyzes a reversible shift of the double bond from the D3-cis to the
D2-trans configuration. The
resulting D2-trans-unsaturated fatty
acyl-CoA is the normal substrate for the next enzyme of the fatty acid
oxidation sequence, enoyl-CoA hydratase,
which hydrates it to form L-3-hydroxyacyl-CoA. The complete oxidation of
oleyl-CoA to nine acetyl-CoA units by the fatty acid oxidation cycle thus requires
an extra enzymatic step catalyzed by the enoyl-CoA
isomerase, in addition to those steps required in the oxidation of
saturated fatty acids.
Polyunsaturated fatty acids, such as
linoleic acid, require a second auxiliary enzyme to complete their oxidation,
since they contain two or more cis
double bonds. When three successive acetyl-CoA units are removed from
linoleyl-CoA, a D3-cis double bond remains, as
in the case of oleyl-CoA. This is then transformed by the enoyl-CoA isomerase
described above to the D2-trans isomer. This undergoes
the usual reactions, with loss of two acetyl-CoA's, leaving an eight-carbon D2-unsaturated
acid. Note, however that the double bond of the latter is in the cis
configuration. Although the D2-cis double bond can be hydrated
by enoyl-CoA hydratase, the product is the D stereoisomer of a
3-hydroxyacyl-CoA, not the L stereoisomer normally formed during oxidation of
saturated fatty acids. Utilization of the d
stereoisomer requires a second auxiliary enzyme, 3-hydroxyacyl-CoA
epimerase, which catalyzes epi-merization at carbon atom 3 to yield the l isomer. The product of this
reversible reaction is then oxidized by the L-specific 3-hydroxyacyl-CoA
dehydrogenase and cleaved by thiolase to complete the oxidation cycle. The remaining
six-carbon saturated fatty acyl-CoA derived from linoleic acid can now be
oxidized to three molecules of acetyl-CoA. These two auxiliary enzymes of the
fatty acid oxidation cycle make possible the complete oxidation of all the
common unsaturated fatty acids found in naturally occurring lipids. The number
of ATP molecules yielded during the complete oxidation of an unsaturated fatty
acid is somewhat lower than for the corresponding saturated fatty acid since
unsaturated fatty acids have fewer hydrogen atoms and thus fewer electrons to
be transferred via the respiratory chain to oxygen.
Oxidation of odd-carbon fatty acids and the
fate of propionyl-CoA
Odd-carbon fatty acids, which are
rare but do occur in some marine organisms, can also be oxidized in the fatty
acid oxidation cycle. Successive acetyl-CoA residues are removed until the
terminal three-carbon residue pro-pionyl-CoA is reached. This compound is also
formed in the oxidative degradation of the amino acids valine and isoleucine.
Propionyl-CoA undergoes enzymatic carboxylation in an ATP-dependent process to
form Ds-methylmaionyl-CoA, a reaction catalyzed by propionyl-CoA
corboxylase. This enzyme contains biotin as its prosthetic group. In the next
step Ds-methylmalonyl-CoA undergoes enzymatic epimerization to LR-methylmalonyl-CoA,
by action of methyimaionyl-CoA racemase. In the next reaction step, catalyzed
by methylmalonyl-CoA mutase, LR-methylmalonyl-CoA
is isomerized to succinyl-CoA, which may then undergo deacylation by reversal
of the succinyl-CoA synthetase reaction
to yield free succinate, an intermediate of the tricarboxylic acid
cycle.
Methylmalonyl-CoA mutase requires as
cofactor coenzyme B12.
Study of this intramolecular reaction with isotope tracers has revealed that
it takes place by the migration of the entire —CO—S—CoA group from carbon atom
2 of methylmalonyl-CoA to the methyl carbon atom in exchange for a hydrogen
atom.
Patients suffering from pernicious
anemia, who are deficient in vitamin B12 because of their lack of
intrinsic factor, excrete large amounts of methylmalonic acid and its precursor
propionic acid in the urine, showing that in such patients the coenzyme B12-dependent
methylmalonyl-CoA mutase reaction is defective.
Glycerol formed in cleavage of
tryacylglycerols enter catabolism or use for biosynthesis of glycerides again.
Before including of glycerol in metabolism it is activated by ATP to
glycerol-3-phosphate by action of glycerol
phosphokinase:
Glycerol Glycerol-3-phosphate
Glycerol-3-phosphate is
oxidized by glycerophosphate
dehydrogenase and glyceroaldehyde-3-phosphate is produced:
Glycerol-3-phosphate Glyceroaldehyde-3-phosphate
Glyceroaldehyde-3-phosphate is
the central metabolite of glycolysis.
The biosynthesis of lipids is a prominent
metabolic process in most organisms. Because of the limited capacity of higher animals
to store polysaccharides, glucose ingested in excess of immediate energy needs
and storage capacity is converted by glycolysis into pyruvate and then
acetyl-CoA, from which fatty acids are synthesized. These in turn are converted
into triacylglycerols, which have a much higher energy content than
polysaccharides and may be stored in very large amounts in adipose or fat
tissues. Triacylglycerols are also stored in the seeds and fruits of many
plants.
The formation of the various phospholipids and
sphingolipids of cell membranes is also an important biosynthetic process.
These complex lipids undergo continuous metabolic turnover in most cells.
Biosynthesis
of saturated fatty acids
The biosynthesis of saturated fatty acids from their ultimate precursor
acetyl-CoA occurs in all organisms but is particularly prominent in the liver,
adipose tissues, and mammary glands of higher animals. It is brought about by a
process that differs significantly from the opposed process of fatty acid
oxidation. In the first place total biosynthesis of fatty acids occurs in the
cytosol, whereas fatty acid oxidation occurs in the mitochondria. Second, the
presence of citrate is necessary for maximal rates of synthesis of fatty acids,
whereas it is not required in fatty acid oxidation. Perhaps the most
unexpected difference is that CO2 is essential for fatty acid
synthesis in cell extracts, although isotopic CO2 is not itself
incorporated into the newly synthesized fatty acids. These and many other
observations have revealed that fatty acid synthesis from acetyl-CoA takes
place with an entirely different set of enzymes from those employed in fatty
acid oxidation.
In the overall reaction of fatty acid
synthesis, which is catalyzed by a complex multienzyme system in the cytosol,
the fatty-acid synthetase complex,
acetyl-CoA derived from carbohydrate or amino acid sources is the ultimate
precursor of all the carbon atoms of the fatty acid chain. However, of the
eight acetyl units required for biosynthesis of palmitic acid, only one is
provided by acetyl-CoA; the other seven arrive in the form of malonyl-CoA,
formed from acetyl-CoA and HCO3- in a carboxylation
reaction. One acetyl residue and seven malonyl residues undergo successive
condensation steps, with release of seven molecules of CO2, to form
palmitic acid; the reducing power is furnished by NADPH:
Acetyl-CoA + 7 malonyl-CoA +
14NADPH + 14H+ ®
CH3(CH2)14COOH + 7CO2 + 8CoA +
14NADP+ + 6H2O
Palmitic acid
The
single molecule of acetyl-CoA required in the process serves as a primer, or
starter; the two carbon atoms of its acetyl group become the two terminal
carbon atoms (15 and 16) of the palmitic acid formed. Chain growth during fatty
acid synthesis thus starts at the carboxyl group of acetyl-CoA and proceeds by
successive addition of acetyl residues at the carboxyl end of the growing
chain. Each successive acetyl residue is derived from two of the three carbon
atoms of a malonic acid residue entering the system in the form of malonyl-CoA;
the third carbon atom of malonic acid, i.e., that of the unesterified carboxyl
group, is lost as CO2. The final product is a molecule of palmitic
acid.
A distinctive feature of the
mechanism of fatty acid biosynthesis is that the acyl intermediates in the
process of chain lengthening are thio esters, not of CoA, as in fatty acid
oxidation, but of a low-molecular-weight conjugated protein called acyl carrier protein (ACP). This protein
can form a complex or complexes with the six other enzyme proteins required for
the complete synthesis of palmitic acid. In most eukariotic cells all seven
proteins of the fatty acid synthetase complex are associated in a multienzymes
cluster.
In
most organisms the end product of the fatty-acid synthetase system is palmitic
acid, the precursor of all other higher saturated fatty acids and of all
unsaturated fatty acids.
The carbon
source for fatty acid synthesis
The ultimate source of all the carbon
atoms of fatty acids is acetyl-CoA, formed in the mitochondria by the oxidative
decarboxylation of pyruvate, the oxidative degradation of some of the amino
acids, or by the b-oxidation of long-chain fatty acids.
Acetyl-CoA itself cannot pass
out of the mitochondria into the cytosol; however, its acetyl group is
transferred through the membrane in other chemical forms. Citrate, formed in
mitochondria from acetyl-CoA and oxaloacetate, may pass through the
mitochondrial membrane to the cytoplasm via the tricarboxylate transport
system. In the cytosol acetyl-CoA is regenerated from citrate by ATP-citrate lyase, also called citrate cleavage enzyme, which catalyzes
the reaction:
In a second pathway the acetyl
group of acetyl-CoA is enzymatically transferred to carnitine, which acts as a
carrier of fatty acids into mitochondria preparatory to their oxidation.
Acetylcarnitine passes from the mitochondrial matrix through the mitochondrial
membrane into the cytosol; acetyl-CoA is then regenerated by transfer of the
acetyl group from acetylcarnitine to cytosol CoA.
Before the acetyl groups of
acetyl-CoA can be utilized by the fatty-acid synthetase complex, an important preparatory
reaction must take place to convert acetyl-CoA into malonyl-CoA, the immediate
precursor of 14 of the 16 carbon atoms of palmitic acid. Malonyl-CoA is formed
from acetyl-CoA and bicarbonate in the cytosol by the action of acetyl-CoA carboxylase, a complex enzyme
that catalyzes the reaction:
Acetyl-CoA
Malonyl-CoA
The carbon atom of the CO2 becomes
the distal or free carboxyl carbon of malonyl-CoA. However, the above equation
give only the overall reaction, the sum of at least three intermediate
reactions.
Acetyl-CoA carboxylase contains biotin as its prosthetic group. The
carboxyl group of biotin is bound in amide linkage to the e-amino group of a specific lysine residue of a
subunit of the enzyme. The covalently bound biotin serves as an intermediate
carrier of a molecule of CO2.
The
reaction catalyzed by acetyl-CoA carboxylase, an allosteric enzyme, is the
primary regulatory, or rate-limiting, step in the biosynthesis of fatty acids.
Acetyl-CoA carboxylase is virtually inactive in the absence of its positive
modulators citrate or isocitrate. The striking allosteric stimulation of this
enzyme by citrate accounts for the fact that citrate is required for fatty
acid synthesis in cell extracts without being used as a precursor.
Acetyl-CoA
carboxylase occurs in both an inactive monomeric form and an active polymeric
form. As it occurs in the avian liver, the inactive enzyme monomer has a
molecular weight of 410,000 and contains one binding site for CO2 (that
is, one biotin prosthetic group), one binding site for acetyl-CoA, and one for
citrate. Citrate shifts the equilibrium between the inactive monomer and the
active polymer, to favor the latter.
Polymeric
acetyl-CoA carboxylase of animal tissues consists of long filaments of enzyme
monomers; each monomer unit contains a molecule of bound citrate. The length of
the polymeric form varies, but on the average each filament contains about 20
monomer units, has a particle weight of some 8 megadaltons, and is about 400 nm
long. Such filaments have been studied in the electron microscope and have
actually been observed in the cytoplasm of adipose cells.
The acetyl-CoA carboxylase
reaction is complex. In fact, the monomeric unit of the enzyme contains four
different subunits. The sequence of reactions in the formation of malonyl-CoA
has been deduced from study of the four subunits of the monomer. One of these
subunits, biotin carboxylase (BC),
catalyzes the first step of the overall reaction, namely, the carboxylation of
the biotin residue covalently bound to the second subunit, which is called biotin
carboxyl-carrier protein (BCCP). The second step in the overall reaction is
catalyzed by the third type of subunit, called carboxyl transferase (CT). In these reactions the biotin residue of
the carboxyl carrier protein serves as a swinging arm to transfer the
bicarbonate ion from the biotin carboxylase subunit to the acetyl-CoA bound to
the active site of the carboxyltransferase subunit. The change from the
inactive monomeric form of acetyl-CoA carboxylase to the polymeric, active form
of the enzyme occurs when citrate is bound to the fourth subunit of each
monomeric unit.
Acyl
carrier protein (ACP)
Acyl carrier protein,
universally symbolized as ACP, was first isolated in pure form from E. coli and
has since been studied from many other sources. The E. coli ACP is a relatively
small (mol wt 10,000), heat-stable protein containing 77 amino acid residues,
whose sequence has been established, and a covalently attached prosthetic
group.
The single sulfhydryl group of
ACP, to which the acyl intermediates are esterified, is contributed by its
prosthetic group, a molecule of 4'-phosphopantetheine,
which is covalently linked to the hydroxyl group of serine residue 36 of the
protein. The 4'-phosphopantetheme moiety is identical with that of coenzyme A,
from which it is derived. The function of ACP in fatty acid synthesis is
analogous to that of CoA in fatty acid oxidation: it serves as an anchor to
which the acyl intermediates are esterified.
The priming reaction
To prime the fatty-acid
synthetase system, acetyl-CoA first reacts with the sulfhydryl group of ACP by
the action of one of the six enzymes of the synthetase system, ACP-acyltransferase, which catalyzes the
reaction:
The malonyl transfer step
In the next reaction, catalyzed by ACP malonyltransferase, malonyl-S-CoA formed in the acetyl-CoA carboxylase reaction reacts with the —SH group of the 4'-phosphopantetheine arm of ACP, with loss of free CoA, to form malonyl-S-ACP:
Malonyl—S—CoA + ACP—SH Û malonyl—S—ACP + CoA—SH
As a result of this step and of the
preceding priming reaction, a malonyl group is now esterified to ACP and an
acetyl group is esterified to an —SH group on the ACP molecule.
The condensation reaction
In the next reaction of the
sequence, catalyzed by b-ketoacyl-ACP synthase, the acetyl group esterified to the
cysteine residue is transferred to carbon atom 2 of the malonyl group on ACP,
with release of the free carboxyl group of the malonyl residue as CO2:
Study of the reaction equilibrium has revealed
the probable basis for the biological selection of malonyl-CoA as the
precursor of two-carbon residues for fatty acid synthesis. If acetoacetyl-CoA
were to be formed from two molecules of acetyl-CoA by the action of acetyl-CoA
acetyltransferase,
Acetyl—S—CoA + acetyl—S—CoA Û acetoacetyl—S—CoA
+ CoA—SH
the
reaction would be endergonic, with its equilibrium lying to the left.
The first reduction reaction
The
acetoacetyl-S-ACP now undergoes reduction by NADPH to form b-hydroxybutyryl-S-ACP. This reaction is catalyzed by b-ketoacyl-ACP
reductase:
The dehydration step
b-Hydroxybutyryl-S-ACP is next dehydrated to the
corresponding unsaturated acyl-S-ACP, namely, crotonyl-S-ACP, by b-hydroxyacyl—ACP-dehydratase:
The second reduction step
Crotonyl-S-ACP is now reduced to butyryl-S-ACP
by enoil-ACP reductase (NADPH); the electron donor is NADPH in
animal tissues:
Crotonyl-S-ACP
Butyryl-S-ACP
This reaction also differs
from the corresponding reaction of fatty acid oxidation in mitochondria in that
a pyridine nucleotide rather than a flavoprotein is involved. Since the
NADPH-NADP+ couple has a more negative standard potential than the
fatty acid oxidizing flavoprotein, NADPH favors reductive formation of the saturated
fatty acid.
The formation of butyryl-ACP completes the first of seven
cycles en route to palmitoyl-S-ACP.
To start the next cycle the butyryl group is transferred from —SH group of
phosphopantetheine to the —SH group of cysteine, thus allowing —SH group of ACP
phosphopantetheine to accept a malonyl group from another molecule of malonyl-CoA.
Then the cycle repeats, the next step
being the condensation of malonyl-S-ACP with butyryl-S-ACP to yield b-ketohexanoyl-S-ACP and CO2.
After seven complete cycles, palmitoyl-ACP is the end product. The
palmitoyl group may be removed to yield free palmitic acid by the action of a thioesterase, or it may be transferred
from ACP to CoA, or it may be incorporated directly into phosphatidic acid in
the pathway to phospholipids and triacylglycerols.
It
is remarkable that in most organisms the fatty-acid synthetase system stops
with the production of palmitic acid and does not yield stearic acid, which has
only two more carbon atoms than palmitic acid and thus does not differ greatly
in physical properties.
Saturated fatty acids having an odd
number of carbon atoms, which are found in many marine organisms, are also made
by the fatty-acid synthetase complex. In this case the synthesis is primed by a
starter molecule of propionyl-S-ACP (instead of acetyl-S-ACP), to which are
added successive two-carbon units via condensations with malonyl-S-ACP.
We
can now write the overall equation for palmitic acid biosynthesis starting from
acetyl-S-CoA:
8 Acetyl—S—CoA + 14NADPH + 14H+ + 7ATP + H2O ®
palmitic acid + 8CoA + 14NADP+ + 7ADP + 7P.
The 14 molecules of NADPH
required for the reductive steps in the synthesis of palmitic acid arise
largely from the NADP-dependent oxidation of
glucose 6-phosphate via the phosphogluconate
pathway. Liver, mammary gland, and adipose tissue of vertebrates, which have a
rather high rate of fatty acid biosynthesis, also have a very active
6-phosphogluconate pathway.
The
enzymatic steps leading to the biosynthesis of palmitic acid differ from those
involved in oxidation of palmitic acid in the following respects:
1. Their intracellular
location.
2. The type of acyl-group
carrier.
3. The form in which the
two-carbon units are added or removed.
4. The pyridine nucleotide
specificity of the b-ketoacyl-b-hydroxyacyl reaction.
5. The stereoisomeric configuration
of the b-hydroxyacyl intermediate.
6. The electron donor-acceptor
system for the crotonyl-butyryl step.
These differences illustrate how two
opposing metabolic processes may proceed independently of each other in the
cell.
Elongation of saturated fatty
acids in mitochondria and microsomes
Palmitic acid, the normal end product of the
fatty-acid synthetase system, is the precursor of the other long-chain saturated
and unsaturated fatty acids in most organisms. Elongation of palmitic acid to
longer-chain saturated fatty acids, of which stearic acid is most abundant, occurs by the action of two
different types of enzyme systems, one in the mitochondria and the other in the
endoplasmic reticulum.
In mitochondria palmitic and other
saturated fatty acids are lengthened by successive additions to the
carboxyl-terminal end of acetyl units in the form of acetyl-CoA; malonyl-ACP
cannot replace acetyl-CoA. The mitochondrial elongation pathway occurs by
reactions similar to those in fatty acid oxidation. Condensation of
palmityl-CoA with acetyl-CoA yields b-ketostearyl-CoA, which is reduced by NADPH to b-hydroxystearyl-CoA. The latter is dehydrated to the unsaturated
stearyl-CoA, which is then reduced to yield stearyl-CoA at the expense of
NADPH. This system will also elongate unsaturated fatty acids.
Microsome
preparations can elongate both saturated and unsaturated fatty acyl-CoA esters,
but in this case malonyl-CoA rather than acetyl-CoA serves as source of the
acetyl groups. The reaction sequence is identical to that in the fatty-acid
synthetase system except that the microsomal system employs CoA and not ACP as
acyl carrier.
Formation
of monoenoic acids
Palmitic and
stearic acids serve as precursors of the two common monoenoic (monounsaturated) fatty acids of animal tissues, namely, poimitoleic and oleic acids, both of which possess a cis double bond in the D9 position. Although most organisms can form
palmitoleic and oleic acids, the pathway and enzymes employed differ between
aerobic and anaerobic organisms. In
vertebrates (and most other aerobic organisms) the D9 double
bond is introduced by a specific monooxygenase system; it is located in the
endoplasmic reticulum of liver and adipose tissue. One molecule of molecular
oxygen (O2) is used as the acceptor for two pairs of electrons, one
pair derived from the palmitoyl-CoA or stearyl-CoA substrate and the other from
NADPH, which is a required coreductant in the reaction. The transfer of electrons
in this complex reaction involves a microsomal electron-transport chain which
carries electrons from NADPH (or NADH) to microsomal cytochrome b5 via cytochrome
b5 reductase, a
flavoprotein. A terminal cyanide-sensitive factor (CSF), a protein, is required
to activate the acyl-CoA and the oxygen.
The overall reaction for
palmitoyl-CoA is:
Palmitoyl—CoA + NADPH + H+
+ O2 ®
palmitoleyl—CoA + NADP+ + 2H2O.
Formation
of polyenoic acids
Bacteria do not contain polyenoic
acids; however, these acids are abundant both in higher plants and in animals.
Mammals contain four distinct families of polyenoic acids, which differ in the
number of carbon atoms between the terminal methyl group and the nearest
double bond. These families are named from their precursor fatty acids,
namely, palmitoleic, oleic, linoleic,
and linolenic acids. All polyenoic acids found in mammals are formed from
these four precursors by further elongation and/or desaturation reactions. Two
of these precursor fatty acids, linoleic and linolenic acids, cannot be
synthesized by mammals and must be obtained from plant sources; they are
therefore called essential fatty acids.
The elongation of chains of polyenoic
acids occurs at the carboxyl end by the mitochondrial or microsomal systems
described above. The desaturation steps occur by the action of the cytochrome b5-oxygenase
system with NADPH as coreductant of oxygen, like the steps in the formation of
palmitoleic and oleic acids, also described above.
Arachidonic acid is the most abundant polyenoic acid. When young rats are placed on
diets deficient in essential fatty acids, they grow slowly and develop a scaly
dermatitis and thickening of the skin. This condition can be relieved by
administration not only of linoleic or linolenic acid but also of arachidonic
acid. The essential fatty acids and some of their derivatives serve as precursors of the prostaglandins.
In
plants linoleic and linolenic acids are synthesized from oleic acid via aerobic
desaturation reactions catalyzed by specific oxygenase systems requiring NADPH
as coreductant.
The
double bonds of naturally occurring fatty acids do not in general undergo
hydrogenation to yield more completely saturated fatty acids; only a few
organisms appear to carry out this process. Unsaturated fatty acids, however,
are completely oxidized by the fatty acid oxidation system.
In most organisms the conversion of saturated to unsaturated fatty acids is promoted by low environmental temperatures. This is an adaptation to maintain the melting point of the total cell lipids below the ambient temperature; unsatu-rated fatty acids have lower melting points than saturated. In some organisms the enzymes involved in fatty acid desaturation increase in concentration in response to low temperatures; in others the unsaturated fatty acids are inserted into lipids at increased rates.
Biosynthesis of triacylglycerols
The triacylglycerols, which function as depot, or storage, lipids, are
actively synthesized in the cells of vertebrates, particularly liver and fat
cells, as well as those of higher plants. Bacteria in general contain
relatively small amounts of triacyglycerols.
In higher animals and plants two
major precursors are required for the synthesis of triacylglycerols: L-glycerol 3-phosphate and fatty acyl-CoA.. L-Glycerol 3-phosphate is derived from two different sources. Its
normal precursor is dihydroxyacetone
phosphate, the product of the aldolase
reaction of glycolysis. Dihydroxyacetone phosphate is reduced to L-glycerol
3-phosphate by the NAD-linked glycerol-
3-phosphate dehydrogenase of the cytosol:
Dihydroxyacetone phosphate + NADH + H+
® L-glycerol 3-phosphate + NAD+
It may also be formed from free glycerol
arising from degradation of triacylglycerols, through the action of glycerol kinase:
ATP + glycerol ® L-glycerol 3-phosphate + ADP
The first stage in
triacyglycerol formation is the acylation of the free hydroxyl groups of
glycerol phosphate by two molecules of fatty acyl-CoA to yield first a lysophosphotidic acid and then a phosphatidic acid:
Glycerol
phosphate Lysophosphotidic
acid
Lysophosphotidic acid Phosphatidic acid
Free glycerol is not acylated.
These reactions occur preferentially with 16- and 18-carbon saturated and
unsaturated acyl-CoA.
Phosphatidic
acids occur only in trace amounts in cells, but they are important
intermediates in the biosynthesis of triacylglycerols and phosphoglycerides.
In the pathway to
triacylglycerols, phosphatidic acid undergoes hydrolysis by phosphatidate phosphatase to form a diacylglycerol:
Phosphatidic acid Diacylglycerol
The diacylglycerol then reacts with a
third molecule of a fatty acyl-CoA to yield a triacylglycerol by the action of diacylglycerol acyltransferase:
Diacylglycerol Triacylglycerol
In the intestinal mucosa of
higher animals, which actively synthesizes triacylglycerols during absorption
of fatty acids from the intestine, another type of acylation reaction comes
into play. Monoacylglycerols formed during intestinal digestion may be
acylated directly by acylglycerol
palmitoyltrans-ferase and thus phosphatidic acid is not an intermediate:
Monoacylglycerol + palmitoyl-CoA ® diacylglycerol + CoA
In
storage fats of animal and plant tissues the triacylglycerols are usually
mixed, i.e., contain two or more different fatty acids.
Catabolism of triacylglycerols
Dietary acylglycerols
undergo hydrolysis in the small intestine by the action of lipases, e.g., those
present in pancreatic juice. Lipase digests the triacylglycerols to
2-monoglycerols, glycerol and free fatty acids. These components are absorbed
and metabolized in the enterocytes, blood and liver. In the enterocytes and
liver the specific for organism acylglycerols are synthesized. Then these are accumulated in adipose tissue and in much smaller quantity in other organs.
Fermentative hydrolysis of in
adipocytes and other cells is implemented in several stages. Diacylglycerols,
monoacylglycerols, glycerol and free fatty acids are formed in this process:
Cholesterol is an extremely important biological molecule that has roles
in membrane structure as well as being a precursor for the synthesis of the steroid
hormones and bile acids.
Both dietary cholesterol and that synthesized de novo are transported
through the circulation in lipoprotein
particles. The same is true of cholesteryl esters, the form in which
cholesterol is stored in cells.
The synthesis
and utilization of cholesterol must be tightly regulated in order to prevent
over-accumulation and abnormal deposition within the body. Of particular
importance clinically is the abnormal deposition of cholesterol and
cholesterol-rich lipoproteins in the coronary arteries. Such deposition,
eventually leading to atherosclerosis, is the leading contributory factor in
diseases of the coronary arteries.
Slightly less than half of the cholesterol in the body derives from
biosynthesis de novo. Biosynthesis in the liver accounts for
approximately 10%, and in the intestines approximately 15%, of the amount
produced each day. Cholesterol synthesis occurs in the cytoplasm and microsomes
(ER) from the two-carbon acetate group of acetyl-CoA.
The
acetyl-CoA utilized for cholesterol biosynthesis is derived from an oxidation
reaction (e.g., fatty acids or pyruvate) in the mitochondria and is transported
to the cytoplasm by the same process as that described for fatty acid synthesis (see the Figure
below). Acetyl-CoA can also be synthesized from cytosolic acetate derived from
cytoplasmic oxidation of ethanol which is initiated by
cytoplasmic alcohol dehydrogenase (ADH3). All the reduction reactions of
cholesterol biosynthesis use NADPH as a cofactor. The isoprenoid intermediates
of cholesterol biosynthesis can be diverted to other synthesis reactions, such
as those for dolichol (used in the synthesis of N-linked glycoproteins,
coenzyme Q (of the oxidative
phosphorylation pathway) or the side chain of heme-a.
Additionally, these intermediates are used in the lipid
modification of some proteins.
Pathway for the movement of acetyl-CoA
units from within the mitochondrion to the cytoplasm for use in lipid and
cholesterol biosynthesis. Note that the cytoplasmic malic enzyme catalyzed
reaction generates NADPH which can be used for reductive biosynthetic reactions
such as those of fatty acid and cholesterol synthesis.
The process of cholesterol synthesis has five major steps:
1. Acetyl-CoAs are converted to
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
2. HMG-CoA is converted to mevalonate
3. Mevalonate is converted to the isoprene
based molecule, isopentenyl pyrophosphate (IPP), with the concomitant loss of
CO2
4. IPP is converted to squalene
5. Squalene is converted to
cholesterol.
Pathway of cholesterol biosynthesis.
Synthesis begins with the transport of acetyl-CoA from the mitochondrion
to the cytosol. The rate limiting step occurs at the
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The
phosphorylation reactions are required to solubilize the isoprenoid
intermediates in the pathway. Intermediates in the pathway are used for the
synthesis of prenylated proteins, dolichol, coenzyme Q and the side chain of
heme a. The abbreviation "PP" (e.g. isopentenyl-PP) stands
for pyrophosphate. Place mouse over intermediate names to see structure.
Acetyl-CoA
units are converted to mevalonate by a series of reactions that begins with the
formation of HMG-CoA. Unlike the HMG-CoA formed during ketone body
synthesis in the mitochondria, this form is synthesized in the
cytoplasm. However, the pathway and the necessary enzymes are similar to those
in the mitochondria. Two moles of acetyl-CoA are condensed in a reversal of the
thiolase reaction, forming acetoacetyl-CoA. The cytoplasmic thiolase enzyme
involved in cholesterol biosynthesis is acetoacetyl-CoA thiolase encoded by the
ACAT2 gene. Although the bulk of acetoacetyl-CoA is derived via this process,
it is possible for some acetoacetate, generated during ketogenesis, to diffuse out of the
mitochondria and be converted to acetoacetyl-CoA in the cytosol via the action
of acetoacetyl-CoA synthetase (AACS). Acetoacetyl-CoA and a third mole of
acetyl-CoA are converted to HMG-CoA by the action of HMG-CoA synthase.
HMG-CoA is
converted to mevalonate by HMG-CoA reductase, HMGR (this enzyme is bound in the
endoplasmic reticulum, ER). HMGR absolutely requires NADPH as a cofactor and
two moles of NADPH are consumed during the conversion of HMG-CoA to mevalonate.
The reaction catalyzed by HMGR is the rate limiting step of cholesterol
biosynthesis, and this enzyme is subject to complex regulatory controls as
discussed below.
Mevalonate is
then activated by two successive phosphorylations (catalyzed by mevalonate
kinase, and phosphomevalonate kinase), yielding 5-pyrophosphomevalonate. In
humans, mevalonate kinase resides in the cytosol indicating that not all the
reactions of cholesterol synthesis are catalyzed by membrane-associated enzymes
as originally described. After phosphorylation, an ATP-dependent
decarboxylation yields isopentenyl pyrophosphate, IPP, an activated isoprenoid
molecule. Isopentenyl pyrophosphate is in equilibrium with its isomer,
dimethylallyl pyrophosphate, DMPP. One molecule of IPP condenses with one
molecule of DMPP to generate geranyl pyrophosphate, GPP. GPP further condenses
with another IPP molecule to yield farnesyl pyrophosphate, FPP. Finally, the
NADPH-requiring enzyme, squalene synthase catalyzes the head-to-tail
condensation of two molecules of FPP, yielding squalene. Like HMGR, squalene
synthase is tightly associated with the ER. Squalene undergoes a two step
cyclization to yield lanosterol. The first reaction is catalyzed by squalene
monooxygenase. This enzyme uses NADPH as a cofactor to introduce molecular oxygen
as an epoxide at the 2,3 position of squalene. Through a series of 19
additional reactions, lanosterol is converted to cholesterol.
The terminal
reaction in cholesterol biosynthesis is catalyzed by the enzyme
7-dehydrocholesterol reductase encoded by the DHCR7 gene. Functional DHCR7
protein is a 55.5 kDa NADPH-requiring integral membrane protein localized to
the microsomal membrane. Deficiency in DHCR7 (due to gene mutations) results in
the disorder called Smith-Lemli-Opitz syndrome, SLOS. SLOS is
characterized by increased levels of 7-dehydrocholesterol and reduced levels
(15% to 27% of normal) of cholesterol resulting in multiple developmental
malformations and behavioral problems.
There are three stage in cholesterol
synthesis. (1) acetic acid is converted to mevalonic acid, (2) mevalonic acid
is converted into squalene, and (3) squalene is converted into cholesterol.
http://www.youtube.com/watch?v=hRx_i9npTDU&feature=related
Mevalonic acid is formed by condensation of three
molecules of acetyl-CoA. The key intermediate in this process is b-hydroxy-b-methylglutaryl-CoA
(HMG-CoA), which is formed as follows:
Acetyl-CoA Acetyl-CoA Acetoacetyl-CoA
b-hydroxy-b-methylglutaryl-CoA
The enzyme is
called b-hydroxy-b-methylglutaryl-CoA synthase.
The b-hydroxy-b-methylglutaryl-CoA
undergoes an irreversible two-step reduction of one of its carboxyl groups to
an alcohol group, with concomitant loss of CoA, by the action of hydroxymethylglutaryl-CoA reductase, to
yield mevalonate:
Mevalonate is phosphorylated by ATP, first to the
5-monophosphate ester and then to the 5-pyrophosphomevalonic acid:
5-pyrophosphomevalonic acid
A third phosphorylation, at carbon atom 3, yields a very unstable
intermediate which loses phosphoric acid and decarboxylates to form 3-isopentenyl pyrophosphate, which
isomerizes to 3,3-dimethylallyl
pyrophosphate.
3,3-dimethylallyl
pyrophosphate
Transport forms of cholesterol
in blood, content of cholesterol in blood, biological role of cholesterol.
LDL are formed in liver and transport
cholesterol from liver to peripheral tissue. LDL is taken up by various tissues
and provides cholesterol, which the tissue utilize.
HDL picks up cholesterol from cell membranes or
from other lipoproteins. Cholesterol is converted to cholesterol esters by the
lecithin:cholesterol acyltransferase (LCAT) reaction. The cholesterol esters
may be transferred to other lipoproteins or carried by HDL to the liver, where
they are hydrolyzed to free cholesterol, which is used for synthesis of VLDL or
converted to bile salts.
The content of cholesterol in blood plasma – 3-8
mmol/l.
Biological role of cholesterol:
-
building blocks of membranes;
-
synthesis of steroid hormones;
-
synthesis of bile acids;
-
synthesis of vitamin D;
-
cholesterol is often deposited on the
inner walls of blood vessels, together with other lipids, a condition known as atherosclerosis, which often
leads to occlusion of blood vessels in the heart and the brain, resulting in
heart attacks and strokes, respectively.
Transport forms of lipids
Certain lipids associate with
specific proteins to form lipoprotein systems in which the specific physical properties of these two classes of biomolecules are blended. In these systems the
lipids and proteins are not covalently joined but are held together largely by
hydrophobic interactions between the nonpolar portions of the lipid and the
protein components.
http://www.youtube.com/watch?v=97uiV4RiSAY
Transport
lipoproteins of blood plasma.
The plasma lipoproteins are
complexes in which the lipids and proteins occur in a relatively fixed ratio.
They carry water-insoluble lipids between various organs via the blood, in a form
with a relatively small and constant particle diameter and weight. Human
plasma lipoproteins occur in four major classes that differ in density as well
as particle size. They are physically distinguished by their relative rates of
flotation in high gravitational fields in the ultracentrifuge.
http://www.youtube.com/watch?v=x-4ZQaiZry8
The
blood lipoproteins serve to transport water-insoluble triacylglycerols and
cholesterol from one tissue to another. The major carriers of triacylglyeerols
are chylomicrons and very low density lipoproteins (VLDL).
The triacylglycerols of the
chylomicrons and VLDL are digested in capillaries by lipoprotein lipase. The
fatty acids that are produced are utilized for energy or converted to
triacylglycerols and stored. The glycerol is used for triacylglycerol synthesis
or converted to DHAP and oxidized for energy, either directly or after
conversion to glucose in the liver. The remnants of the chylomicrons are taken
up by liver cells by the process of endocytosis and are degraded by lysosomal
enzymes, and the products are reused by the cell.
VLDL is
converted to intermediate density lipoproteins (IDL), which is degraded by
the liver or converted in blood capillaries to low density lipoproteins LDL by further digestion of
triacylglycerols.
LDL is taken up by various tissues
and provides cholesterol, which the tissue utilize
High density
lipoproteins (HDL) which is synthesized by the liver,
transfers apoproteins to ehylomicrons and VLDL.
HDL
picks up cholesterol from cell membranes or from other lipoproteins.
Cholesterol is converted to cholesterol esters by the lecithin:cholesterol
acyltransferase (LCAT) reaction. The cholesterol esters may be transferred to
other lipoproteins or carried by HDL to the liver, where they are hydrolyzed to
free cholesterol, which is used for synthesis of VLDL or converted to bile
salts.
Composition of the blood lipoproteins
The major components of lipoproteins
are triacylglycerols, cholesterol, cholesterol esters, phospholipids, and
proteins. Purified proteins (apoproteins) are designated A, B, C, and E.
Component Chylomicrons VLDL IDL LDL HDL
Triacylglycerol 85% 55% 26% 10% 8%
Protein 2% 9% 11% 20% 45%
Type B,C,E B,C,E B,E B A,C,E
Cholesterol 1% 7% 8% 10% 5%
Cholesterol ester 2% 10% 30% 35% 15%
Phospholipid 8% 20% 23% 20% 25%
Chylomicrons are the
least dense of the blood lipoproteins because they have the most
triacylglycerol and the least protein.
VLDL is more dense than chylomicrons but still has a high
content of triacylglycerol.
IDL, which is derived from VLDL, is more dense than chylomicrons but still has a high content
of triacylglycerol.
LDL has less triacylglycerol and more protein
and, therefore, is more dense than the IDL from which it is derived. LDL has
the highest content of cholesterol and its esters.
HDL is the most dense lipoprotein. It has the
lowest triacylglycerol and the highest protein content.
http://www.youtube.com/watch?v=XLLBlBiboJI&feature=related
Metabolism
of Chylomicrons
Chylomicrons are synthesized in intestinal
epithelial cells. Their triacylglycerols are derived from dietary lipid, and
their major apoprotein is apo B-48.Chylomicrons travel through the lymph into
the blood. In peripheral tissues,
particularly adipose and muscle, the triacylglyerols are digested by lipoprotein
lipase.The chylomicron remnants interact with receptors on liver cells and
are taken+ up by endocytosis. The contents are degraded by lysosomal enzymes, and the products
(amino acids, fatty acids, glycerol, and cholesterol) are released into the
cytosol and reutilized.
Metabolism of VLDL
VLDL is
synthesized in the liver, particularly after a
high-carbohydrate meal. It is formed from triacylglycerols that are package
with cholesterol, apoproteins (particularly apo B-100), and phospholipids and
it is released into the blood.
In peripheral tissues, particularly
adipose and muscle, VLDL triacylglycerols are digested by lipoprotein lipase,
and VLDL is converted to IDL.
IDL returns to the liver, is
taken up by endocytosis, and is degraded by lysosomal enzymes.
IDL may
also be further degraded by lipoprotein lipase, forming LDL.
LDL reacts with receptors on various cells, is
taken up by endocytosis and is digested by
lysosomal enzymes.
Cholesterol,
released from cholesterol esters by a lysosomal esterase, can be used for the
synthesis of cell memmbranes or bile salts in the liver or steroid hormones in
endocrine tissue.
http://www.youtube.com/watch?v=XPguYN7dcbE
Metabolism of HDL.
HDL is synthesized by the liver and released into the blood as
disk-shaped particles. The major protein of HDL is apo A.
HDL cholesterol, obtained from cell membranes or from other
lipoproteins, is converted to cholesterol esters. As cholesterol esters
accumulate in the core of the lipoprotein, HDL particles become spheroids.
HDL particles are taken up by the liver by endocytosis and hydrolyzed by
lysosomal enzymes. Cholesterol, released from cholesterol esters may be
packaged by the liver in VLDL and released into the blood or converted to bile
salts and secreted into the bile.
Normal
healthy adults synthesize cholesterol at a rate of approximately 1g/day and
consume approximately 0.3g/day. A relatively constant level of cholesterol in
the blood (150–200 mg/dL) is maintained primarily by controlling the level of de
novo synthesis. The level of cholesterol synthesis is regulated in part by
the dietary intake of cholesterol. Cholesterol from both diet and synthesis is
utilized in the formation of membranes and in the synthesis of the steroid hormones and bile acids. The greatest proportion of
cholesterol is used in bile acid synthesis.
The cellular
supply of cholesterol is maintained at a steady level by three distinct
mechanisms:
1. Regulation of HMGR activity and levels
2. Regulation of excess intracellular free cholesterol through the activity
of acyl-CoA:cholesterol acyltransferase, ACAT
3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake
and HDL-mediated reverse transport.
Regulation of
HMGR activity is the primary means for controlling the level of cholesterol
biosynthesis. The enzyme is controlled by four distinct mechanisms: feed-back
inhibition, control of gene expression, rate of enzyme degradation and
phosphorylation-dephosphorylation.
The first
three control mechanisms are exerted by cholesterol itself. Cholesterol acts as
a feed-back inhibitor of pre-existing HMGR as well as inducing rapid
degradation of the enzyme. The latter is the result of cholesterol-induced
polyubiquitination of HMGR and its degradation in the proteosome (see proteolytic degradation below). This
ability of cholesterol is a consequence of the sterol sensing domain,
SSD of HMGR. In addition, when cholesterol is in excess the amount of
mRNA for HMGR is reduced as a result of decreased expression of the gene. The
mechanism by which cholesterol (and other sterols) affect the transcription of
the HMGR gene is described below under regulation of sterol content.
Regulation of
HMGR through covalent modification occurs as a result of phosphorylation and
dephosphorylation. The enzyme is most active in its unmodified form.
Phosphorylation of the enzyme decreases its activity. HMGR is phosphorylated by
AMP-activated protein kinase, AMPK (this is not the same as
cAMP-dependent protein kinase, PKA). AMPK itself is activated via
phosphorylation. Phosphorylation of AMPK is catalyzed by at least 2 enzymes.
The primary kinase sensitive to rising AMP levels is LKB1. LKB1 was first
identified as a gene in humans carrying an autosomal dominant mutation in Peutz-Jeghers
syndrome, PJS. LKB1 is also found mutated in lung adenocarcinomas. The second
AMPK phosphorylating enzyme is calmodulin-dependent protein kinase kinase-beta
(CaMKKβ). CaMKKβ induces phosphorylation of AMPK in response to
increases in intracellular Ca2+ as a result of muscle contraction.
Visit AMPK: The Master Metabolic Regulator for
more detailed information on the role of AMPK in regulating metabolism.
Regulation of
HMGR by covalent modification. HMGR is most active in the dephosphorylated
state. Phosphorylation is catalyzed by AMP-activated protein kinase, AMPK,
(used to be termed HMGR kinase), an enzyme whose activity is also regulated by
phosphorylation. Phosphorylation of AMPK is catalyzed by at least 2 enzymes:
LKB1 and CaMKKβ. Hormones such as glucagon and epinephrine negatively
affect cholesterol biosynthesis by increasing the activity of the inhibitor of
phosphoprotein phosphatase inhibitor-1, PPI-1. Conversely, insulin stimulates
the removal of phosphates and, thereby, activates HMGR activity. Additional
regulation of HMGR occurs through an inhibition of its' activity as well as of
its' synthesis by elevation in intracellular cholesterol levels. This latter
phenomenon involves the transcription factor SREBP described below.
The activity of HMGR is additionally
controlled by the cAMP signaling pathway. Increases in cAMP lead to activation
of cAMP-dependent protein kinase, PKA. In the context of HMGR regulation, PKA
phosphorylates phosphoprotein phosphatase inhibitor-1 (PPI-1) leading to an
increase in its' activity. PPI-1 can inhibit the activity of numerous
phosphatases including protein phosphatase
Since the intracellular level of cAMP is regulated by hormonal stimuli,
regulation of cholesterol biosynthesis is hormonally controlled. Insulin leads
to a decrease in cAMP, which in turn activates cholesterol synthesis.
Alternatively, glucagon and epinephrine, which increase the level of cAMP,
inhibit cholesterol synthesis.
The ability of insulin to stimulate, and glucagon to inhibit, HMGR
activity is consistent with the effects of these hormones on other metabolic
pathways. The basic function of these two hormones is to control the
availability and delivery of energy to all cells of the body.
Long-term control of HMGR activity is exerted primarily through control
over the synthesis and degradation of the enzyme. When levels of cholesterol
are high, the level of expression of the HMGR gene is reduced. Conversely,
reduced levels of cholesterol activate expression of the gene. Insulin also
brings about long-term regulation of cholesterol metabolism by increasing the
level of HMGR synthesis.
The stability of HMGR is regulated as the rate of flux through the
mevalonate synthesis pathway changes. When the flux is high the rate of HMGR
degradation is also high. When the flux is low, degradation of HMGR decreases.
This phenomenon can easily be observed in the presence of the statin drugs as
discussed below.
HMGR is
localized to the ER and like SREBP (see below) contains a sterol-sensing
domain, SSD. When sterol levels increase in cells there is a concomitant
increase in the rate of HMGR degradation. The degradation of HMGR occurs within
the proteosome, a multiprotein complex
dedicated to protein degradation. The primary signal directing proteins to the
proteosome is ubiquitination. Ubiquitin is a 7.6kDa protein that is covalently
attached to proteins targeted for degradation by ubiquitin ligases. These enzymes
attach multiple copies of ubiquitin allowing for recognition by the proteosome.
HMGR has been shown to be ubiquitinated prior to its degradation. The primary
sterol regulating HMGR degradation is cholesterol itself. As the levels of free
cholesterol increase in cells, the rate of HMGR degradation increases.
Cholesterol
is transported in the plasma predominantly as cholesteryl esters associated
with lipoproteins.
Dietary cholesterol is transported from the small intestine to the liver within
chylomicrons. Cholesterol synthesized by the liver, as well as any dietary
cholesterol in the liver that exceeds hepatic needs, is transported in the
serum within LDLs. The liver synthesizes VLDLs and these are converted to LDLs
through the action of endothelial cell-associated lipoprotein lipase.
Cholesterol found in plasma membranes can be extracted by HDLs and esterified
by the HDL-associated enzyme LCAT. The cholesterol acquired from peripheral
tissues by HDLs can then be transferred to VLDLs and LDLs via the action of
cholesteryl ester transfer protein (apo-D) which is associated with HDLs. Reverse
cholesterol transport allows peripheral cholesterol to be returned to
the liver in LDLs. Ultimately, cholesterol is excreted in the bile as free
cholesterol or as bile salts following conversion to bile acids in the liver.
Nutrition and health
Lipids
play diverse and important roles in nutrition and health. Many lipids are absolutely essential for life, however, there is also considerable awareness that abnormal levels of
certain lipids, particularly cholesterol (in hypercholesterolemia) and, more recently, trans fatty acids, are risk factors for heart disease and other diseases. We need fats in our bodies
and in our diet. Animals in general use fat for energy storage because fat
stores 9 KCal/g of energy.
Plants, which don’t move
around, can afford to store food for energy in a less compact but more easily accessible
form, so they use starch (a carbohydrate, NOT A LIPID) for energy storage.
Carbohydrates and proteins store only 4 KCal/g of energy, so fat stores over
twice as much energy/gram as other sources of energy.
We need fats in our bodies and in our diet. Animals in general use fat for energy storage
because fat stores 9 KCal/g of energy. Plants, which don’t move around, can
afford to store food for energy in a less compact but more easily accessible
form, so they use starch (a carbohydrate, NOT A LIPID) for energy storage. Carbohydrates
and proteins store only 4 KCal/g of energy, so fat stores over twice as much
energy/gram as fat. By the way, this is also related to the idea behind some of
the high-carbohydrate weight loss diets.
http://www.youtube.com/watch?v=-WhADd1GKtA&feature=relmfu
The human body burns carbohydrates and fats for fuel
in a given proportion to each other. The theory behind these diets is that if they
supply carbohydrates but not fats, then it is hoped that the fat needed to
balance with the sugar will be taken from the
dieter’s body stores. Fat is also is used in our bodies to a) cushion vital
organs like the kidneys and b) serve as insulation, especially just beneath the
skin.
http://www.youtube.com/watch?v=_TR8vUFP_O4&feature=related
The importance of obesity, a sedentary lifestyle, very high
fat diet, and intake of large concentrations of refined carbohydrates should
not be underestimated as causes of severe hypertriglyceridemia. Instituting a
program of progressive aerobic and toning exercise, weight loss, and dietary
management can significantly lower triglyceride levels and, in some cases,
normalize them.
During pregnancy, severe hypertriglyceridemia is an
unusual complication and may cause pancreatitis.
·
Many case reports have been published
describing interventions to manage this condition.
·
Most commonly, a very low-fat diet was
sufficient to control triglycerides and prevent pancreatitis.
·
Intermittent and, in persistent cases,
continuous total parenteral nutrition has been used—usually in the third
trimester.
To treat hyperlipidemia, a diet low in total fat, saturated
fat, and cholesterol is recommended, along with reducing or avoiding alcohol
intake. The American Heart Association (AHA) endorses the following dietary
recommendations for people with high blood cholesterol:
·
Total fat: 25% of total calories
·
Saturated fat: less than 7% total calories
·
Polyunsaturated fat: up to 10% total calories
·
Monounsaturated fat: up to 20% total calories
·
Carbohydrates: 50-60% total calories
·
Protein: ~15% total calories
·
Cholesterol: less than 200 mg/dL
·
Plant sterols:
·
Soluble fiber such as psyllium: 10- 25g
Categories of
appropriate foods include:
·
Lean meat/fish: less than 5 oz/day
·
Eggs: less than 2 yolks per week (whites unlimited)
·
Low fat dairy products (<1% fat): 2-3 servings/day
·
Grains, especially whole grains: 6-8 tsp/day
·
Vegetables: less than 6 servings per day
·
Fruits: 2-5 servings per day
These
recommendations translate into the following practical dietary guidelines:
·
Select only the leanest meats, poultry, fish and shellfish. Choose
chicken and turkey without skin or remove skin before eating. Some fish, like
cod, have less saturated fat than either chicken or meat.
·
Limit goose and duck. They are high in saturated fat, even with
the skin removed.
·
Some chicken and turkey hot dogs are lower in saturated fat and
total fat than pork and beef hot dogs. There are also lean beef hot dogs and
vegetarian (tofu) franks that are low in fat and saturated fat.
·
Dry peas, beans and tofu can be used as meat substitutes that are
low in saturated fat and cholesterol. Dry peas and beans also have a lot of
fiber, which can help to lower blood cholesterol.
·
Egg yolks are high in dietary cholesterol. A yolk contains about
213 mg. They should be limited to no more than 2 per week, including the egg
yolks in baked goods and processed foods. Egg whites have no cholesterol, and
can be substituted for whole eggs in recipes.
·
Like high fat meats, regular dairy foods that contain fat, such as
whole milk, cheese, and ice cream, are also high in saturated fat and
cholesterol. However, dairy products are an important source of nutrients and the
diet should include 2 to 3 servings per day of low-fat or nonfat dairy
products.
·
When shopping for hard cheeses, select them fat-free, reduced fat,
or part skim.
·
Select frozen desserts that are lower in saturated fat, such as
ice milk, low-fat frozen yogurt, low-fat frozen dairy desserts, sorbets, and
popsicles.
·
Saturated fats should be replaced with unsaturated fats. Select
liquid vegetable oils that are high in unsaturated fats, such as canola, corn,
olive, peanut, saf-flower, sesame, soybean, and sunflower oils.
·
Limit butter, lard, and solid shortenings. They are high in
saturated fat and cholesterol.
·
Select light or nonfat mayonnaise and salad dressings.
·
Fruits and vegetables are very low in saturated fat and total fat,
and have no cholesterol. Fruits and vegetables should be eaten as snacks,
desserts, salads, side dishes, and main dishes.
·
Breads, cereals, rice, pasta, grains, dry beans, and peas are high
in starch and fiber and low in saturated fat and calories. They also have no
dietary cholesterol, except for some bakery breads and sweet bread products
made with high fat, high cholesterol milk, butter and eggs.
·
Select whole grain breads and rolls whenever possible. They have
more fiber than white breads.
·
Most dry cereals are low in fat. Limit high-fat granola, muesli,
and cereal products made with coconut oil and nuts, which increases the
saturated fat content.
·
Limit sweet baked goods that are made with saturated fat from
butter, eggs, and whole milk such as croissants, pastries, muffins, biscuits, butter
rolls, and doughnuts.
·
Snacks such as cheese crackers, and some chips are often high in
saturated fat and cholesterol. Select rather low-fat ones such as bagels, bread
sticks, cereals without added sugar, frozen grapes or banana slices, dried
fruit, non-oil baked tortilla chips, popcorn or pretzels.
Metabolism
of ketonе bodies
http://www.youtube.com/watch?v=mLi9SEIrbuc&feature=related
In many vertebrates
the liver has the enzymatic capacity to divert some of the acetyl-CoA derived
from fatty acid or pyruvate oxidation, presumably during periods of excess formation,
into free acetoacetate and b-hydroxybutyrate,
which are transported via the blood to the peripheral tissues, where they may
be oxidized via the tricarboxylic acid cyrcle.
These
compounds, together with acetone, are collectively called the ketone bodies.
acetoacetate b-hydroxybutyrate acetone
Ketogenesis: mechanism, localization, biological role.
Free acetoacetate, which is the primary source of the other ketone
bodies, is formed from acetoacetyl-CoA. Some of the acetoacetyl-CoA arises from
the last four carbon atoms of a long-chain fatty acid after oxidative removal
of successive acetyl-CoA residues in the mitochondrial matrix. However, most
of the acetoacetyl-CoA formed in the liver arises from the head-to-tail
condensation of two molecules of acetyl-CoA derived from fatty acid oxidation
by the action of acetyl-CoA
acetyltransferase:
acetyl-CoA acetyl-CoA acetoacetyl-CoA
The
acetoacetyl-CoA formed in these reactions then undergoes loss of CoA, a
process called deacylation, to yield
free acetoacetate in a special pathway taking place in the mitochondrial
matrix. It involves the enzymatic formation and cleavage of b-hydroxy-b-methylglutaryl-CoA, an intermediate which also serves
as a precursor of sterols.
acetoacetyl-CoA acetyl-CoA b-hydroxy-b-methylglutaryl-CoA
b-hydroxy-b-methylglutaryl-CoA acetoacetate acetyl-CoA
The free acetoacetate so produced is enzymatically reduced to D-b-hydroxybutyrate by the NAD-linked b-hydroxybutyrate dehydrogenase, which is located in the inner mitochondrial membrane.
acetoacetate b-hydroxybutyrate
The mixture of free acetoacetate and b-hydroxybutyrate
resulting from these reactions may diffuse out of the liver cells into the
bloodstream, to be transported to the peripheral tissues.
The mechanism of acetoacetate utilizing in tissues (ketolysis).
In the
peripheral tissues the b-hydroxybutyrate
is oxidized to acetoacetate, which is then activated by transfer of CoA from
succinyl-CoA. The succinyl-CoA required arises from the oxidation of a-ketoglutarate.
Another way of acetoacetate activation in peripheral
tissues is the direct interaction of acetoacetate with ATP and CoA-SH:
The acetoacetyl-CoA formed in the peripheral tissues
by these reactions then undergoes thiolytic cleavage to two molecules of
acetyl-CoA, which then may enter the tricarboxylic acid cycle.
The mechanism
of the increase of ketone bodies content in blood at diabetus mellitus and
starvation.
Normally the concentration of
ketone bodies in the blood is rather low (10-20 mg/l), but in fasting or in the
disease diabetes mellitus, it may reach very high levels. This condition, known
as ketosis, arises when the rate of
formation of the ketone bodies by the liver exceeds the capacity of the peripheral
tissues to utilize them, with a resulting accumulation in the blood and
excretion via the kidneys (in normal the content of ketone bodies in urine is
up to 50 mg/day).
The utilization of acetyl-CoA in
tricarboxylic acid cycle depends on the availability of oxaloacetate in cell.
The formation of oxaloacetate depends on quantity of pyruvate, which is formed
from glucose. In fasting or diabetus mellitus the entering of glucose into
cells is inhibited, oxaloacetate enters the gluconeogenesis process and is not
available for the interaction with acetyl CoA in citrate synthase reaction. In
this metabolic state acetyl-CoA is used for the ketone bodies formation. The
accumulation of ketone bodies is also promotted by b-oxidation of fatty acids due to the stimulation of lipolysis in adipose
tissue in glucose starvation conditions.
The effect of nervous system on lipid metabolism.
Sympathetic nervous system
activates the splitting of triacylglycerol (lipolysis) and oxidation of fatty
acids.
Parasympathetic nervous system
promotes the synthesis of lipids and cholesterol in organism.
Endocrine regulation of lipid metabolism.
The effect of somatotropic
hormone on lipid metabolism:
-
stimulates lipolysis;
-
stimulates the oxidation of fatty
acids.
Prolactin.
- stimulates synthesis of lipids
in mammary glands.
Lipotropic
hormone.
- stimulates the mobilization of lipids from
depot.
Thyroxine and triiodthyronine.
-
activate
the lipid oxidation and mobilization.
Insulin.
- enhances the synthesis of lipids;
- promotes the lipid storage activating the
carbohydrate decomposition;
-
inhibits the gluconeogenesis.
Glucagon.
- activates the
lipolisis;
Lipocain.
- activates the formation of phospholipids in
liver and stimulates the action of lipotropic alimentary factors;
-
activates the oxidation of fatty
acids in liver.
Epinephrine.
-
activates the tissue lipase, mobilization of
lipids and oxidation of fatty acids.
Glucocorticoids.
-
promote the absorption of
lipids in intestine;
-
activate lipolysis;
-
activate the conversion of
fatty acids in carbohydrates.
Sex hormones.
-
enhance the oxidation of
lipids;
-
inhibit the synthesis of
cholesterol.
Interrelationship of carbohydrate and lipid metabolism.
Transformation of carbohydrates to lipids.
2. Biosynthesis of fatty acids takes place from acetyl-CoA which is
formed in oxidative decarboxilation of pyruvate. Pyruvate is the central
intermediate product of carbohydrate metabolism.
3. Carbohydrates are also source of hydrogen atoms, which are necessary
for fatty acids synthesis. For this purpose the hydrogen atoms of reduced
coenzymes NADPH2 are used. NADPH2 are usually produced in
pentose phosphate cycle.
Transformation of lipids to
carbohydrates.
The formation of carbohydrates from other compounds
is called gluconeogenesis.
2. Small amount of carbohydrates can be also
synthesised from glycerol by means of its oxidation to dihydroxiacetone
monophosphate and glycerolaldehyde phosphate, which are the intermediates
metabolites of glycolysis.
DISORDERS OF LIPID METABOLISM
Hyperlipidemia, hyperlipoproteinemia, or
hyperlipidaemia (British English) involves abnormally elevated levels of
any or all lipids
and/or lipoproteins
in the blood.
It is the most common form of dyslipidemia
(which also includes any decreased lipid levels).
Lipids (fat-soluble molecules) are transported in a protein
capsule.
The size of that capsule, or lipoprotein, determines its density. The
lipoprotein density and type of apolipoproteins
it contains determines the fate of the particle and its influence on metabolism.
Hyperlipidemias are divided in primary and secondary
subtypes. Primary hyperlipidemia is usually due to genetic causes (such as a
mutation in a receptor protein), while secondary hyperlipidemia arises due to
other underlying causes such as diabetes.
Lipid and lipoprotein abnormalities are common in the general population, and
are regarded as a modifiable risk factor for cardiovascular disease due to their
influence on atherosclerosis. In addition, some forms may
predispose to acute pancreatitis.
Hyperlipidemias may basically be classified as either
familial (also called primary) caused by specific genetic abnormalities, or
acquired (also called secondary)
when resulting from another underlying disorder that leads to alterations in
plasma lipid and lipoprotein metabolism. Also, hyperlipidemia may be
idiopathic, that is, without known cause.
Hyperlipidemias are also classified according to which
types of lipids are elevated, that is hypercholesterolemia, hypertriglyceridemia or both in combined hyperlipidemia. Elevated levels
of Lipoprotein(a)
may also be classified as a form of hyperlipidemia.
Familial hyperlipidemias are classified according to the Fredrickson classification which is
based on the pattern of lipoproteins on electrophoresis
or ultracentrifugation. It was later adopted by
the World Health Organization (WHO). It does
not directly account for HDL, and it does not distinguish among the
different genes
that may be partially responsible for some of these conditions. It remains a
popular system of classification, but is considered dated by many.
Relative prevalence of familial forms of hyperlipoproteinemia
Type I hyperlipoproteinemia exists in several forms:
·
Lipoprotein lipase deficiency (Type Ia),
due to a deficiency of lipoprotein lipase (LPL) or altered apolipoprotein
C2, resulting in elevated chylomicrons,
the particles that transfer fatty acids from the digestive
tract to the liver.
·
Familial apoprotein CII deficiency (Type
Ib), a condition caused by a lack of lipoprotein lipase activator.
·
Chylomicronemia due to circulating inhibitor
of lipoprotein lipase (Type Ic)
Type I hyperlipoproteinemia usually presents in childhood
with eruptive xanthomata and abdominal colic. Complications include retinal
vein occlusion, acute pancreatitis, steatosis and organomegaly, and lipaemia
retinalis.
Hyperlipoproteinemia type II, by far the most common
form, is further classified into type IIa and type IIb, depending mainly on
whether there is elevation in the triglyceride level in addition to LDL
cholesterol.
Main article: Familial hypercholesterolemia
This may be sporadic (due to dietary factors), polygenic,
or truly familial as a result of a mutation either in the LDL receptor
gene on chromosome 19 (0.2% of the population) or the ApoB
gene (0.2%). The familial form is characterized by tendon
xanthoma, xanthelasma and premature cardiovascular
disease. The incidence of this disease is about
The high VLDL levels are due to overproduction of substrates,
including triglycerides, acetyl CoA, and an increase in B-100 synthesis. They
may also be caused by the decreased clearance of LDL. Prevalence in the
population is 10%.
·
Familial combined hyperlipoproteinemia
(FCH)
·
Lysosomal acid lipase deficiency,
often called (Cholesteryl ester storage disease)
·
Secondary combined hyperlipoproteinemia
(usually in the context of metabolic syndrome, for which it is a
diagnostic criterion)
This form is due to high chylomicrons
and IDL (intermediate density lipoprotein). Also known as broad beta disease
or dysbetalipoproteinemia, the most common cause for this form is the
presence of ApoE E2/E2 genotype. It is due to
cholesterol-rich VLDL (β-VLDL). Its prevalence has been estimated to be
approximately
Familial hypertriglyceridemia is an
autosomal dominant condition occurring in approximately 1% of the population.[6]
Hyperlipoproteinemia type V is very similar to type I,
but with high VLDL
in addition to chylomicrons.
It is also associated with glucose intolerance and
hyperuricemia
Non-classified forms are extremely rare:
·
Polygenic hypercholesterolemia
Acquired hyperlipidemias (also called secondary
dyslipoproteinemias) often mimic primary forms of hyperlipidemia and can have
similar consequences.[2]
They may result in increased risk of premature atherosclerosis
or, when associated with marked hypertriglyceridemia, may lead to pancreatitis
and other complications of the chylomicronemia syndrome.[2]
The most common causes of acquired hyperlipidemia are:
·
Use of drugs such as diuretics,[2]
beta blockers,[2]
and estrogens[2]
Other conditions leading to acquired hyperlipidemia
include:
·
Hypothyroidism[2]
·
Some rare endocrine disorders[2]
and metabolic disorders[2]
Treatment of the underlying condition, when possible, or
discontinuation of the offending drugs usually leads to an improvement in the
hyperlipidemia. Specific lipid-lowering therapy may be required in certain
circumstances.
Another acquired cause of hyperlipidemia, although not
always included in this category, is postprandial hyperlipidemia, a normal
increase following ingestion of food[12]
For treatment of type II, dietary modification is the
initial approach but many patients require treatment with statins
(HMG-CoA reductase inhibitors) to reduce cardiovascular risk. If the
triglyceride level is markedly raised, fibrates
may be preferable due to their beneficial effects. Combination treatment of
statins and fibrates, while highly effective, causes a markedly increased risk
of myopathy
and rhabdomyolysis
and is therefore only done under close supervision. Other agents commonly added
to statins are ezetimibe, niacin and bile acid sequestrants. Dietary
supplementation with fish oil is also used to reduce elevated triglycerides,
with the greatest effect occurring in patients with the greatest severity.[13]
There is some evidence for benefit of plant sterol-containing products and ω3-fatty acids[14]
Familial dysbetalipoproteinemia or type III
hyperlipoproteinemia (also known as "remnant hyperlipidemia",
"remnant hyperlipoproteinaemia", "broad beta disease"[1]
and "remnant removal disease"[1])
is a condition characterized by increased LDL, cholesterol,
and triglyceride
levels, and decreased HDL levels.[2]:534