METABOLISM OF LIPIDS:
DIGESTION, ABSORPTION, RESYNTHESIS IN THE INTESTINAL WALL
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 func¬tions 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 func¬tions, serving
(1) as structural components of membranes,
(2) as storage and transport forms of metabolic fuel,
(3) as a pro¬tective 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 bio¬molecules 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 proper¬ties of their components are blended to
fill specialized bio¬logical functions.
Classification of lipids
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
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 D 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 16:1D9).
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 pal¬mitic 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
pre¬dominate. 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 satu¬rated 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 10. In most
polyunsaturated (polyenoic) fatty acids one double bond is between carbon atoms
9 and 10; the addi¬tional double bonds usually occur between the 9,10 double
bond and the methyl-terminal end of the chain. In most types of polyunsaturated
fatty acids the double bonds are separated by one methylene group, for example,
—CH=CH—CH2—CH=CH—; only in a few types of plant fatty acids are the double
bonds in conjugation, that is, —CH=CH—CH=CH—. The double bonds of nearly all
kinds of naturally occurring unsaturated fatty acids are in the cis geometrical
configuration; only a very few are trans.
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.
Some naturally occuring fatty acids
Symbol Structure Systemic name Common name
Saturated fatty acid
Ñ12:0 ÑÍ3(ÑÍ2)10ÑÎÎÍ n-Dodecanoic Lauric
Ñ14:0 ÑÍ3(ÑÍ2)12ÑÎÎÍ n-Tetradecanoic Myristic
Ñ16:0 ÑÍ3(ÑÍ2)14ÑÎÎÍ n-Hexadecanoic Palmitic
Ñ18:0 ÑÍ3(ÑÍ2)16ÑÎÎÍ n-Octadecanoic Stearic
Ñ20:0 ÑÍ3(ÑÍ2)18ÑÎÎÍ n-Eicosanoic Arachidic
Ñ22:0 ÑÍ3(ÑÍ2)20ÑÎÎÍ n-Docosanoic Begenic
Ñ24:0 ÑÍ3(ÑÍ2)22ÑÎÎÍ n-Tetracosanoic Lignoceric
Unsaturated monoenic fatty acid
Ñ16:1 ÑÍ3(ÑÍ2)5ÑÍ=ÑÍ(ÑÍ2)7ÑÎÎÍ Palmitooleic
Ñ18:1 ÑÍ3(ÑÍ2)7ÑÍ=ÑÍ(ÑÍ2)7ÑÎÎÍ Oleic
Unsaturated polienic fatty acid
Ñ18:2 ÑÍ3(ÑÍ2)4(ÑÍ=ÑÍÑÍ2)2(ÑÍ2)6ÑÎÎÍ Linoleic
Ñ18:3 ÑÍ3ÑÍ2(ÑÍ=ÑÍÑÍ2)3(ÑÍ2)6ÑÎÎÍ Linolenic
Ñ20:4 ÑÍ3(ÑÍ2)4(ÑÍ=ÑÍÑÍ2)4(ÑÍ2)2ÑÎÎÍ 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 ulti¬mately die with many
pathological signs. When linoleic acid is present in the diet, these conditions
do not develop. Lino¬lenic 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 pre¬cursors in the biosynthesis of a group of fatty acid
deriva¬tives called prostaglandins, hormonelike com¬pounds 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 conforma¬tions 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 con¬tributed by the nonrotating double bond(s).
Unsaturated fatty acids undergo addition reactions at their double bonds.
Quantitative titration with halogens, e.g., io¬dine 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 re¬ferred 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
recom¬mended 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 com¬ponents 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 triacyl¬glycerols 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 in¬creases 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 appre¬ciable 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 biologi¬cally. 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
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 hydro¬carbon
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 2 g of cholesterol per day, and that makes up about 85% of blood cholesterol,
while only about 15% comes from dietary sources. Cholesterol is the precursor
to our sex hormones and Vitamin D. Vitamin D is formed by the action of UV
light in sunlight on cholesterol molecules that have “risen” to near the
surface of the skin. At least one source I read suggested that people not
shower immediately after being in the sun, but wait at least ½ hour for
the new Vitamin D to be absorbed deeper into the skin. Our cell membranes
contain a lot of cholesterol (in between the phospholipids) to help keep them
“fluid” even when our cells are exposed to cooler temperatures.
Many people have hear the claims that egg yolk contains too much
cholesterol, thus should not be eaten. An interesting study was done at Purdue
University a number of years ago to test this. Men in one group each ate an egg
a day, while men in another group were not allowed to eat eggs. Each of these
groups was further subdivided such that half the men got “lots” of exercise
while the other half were “couch potatoes.” The results of this experiment
showed no significant difference in blood cholesterol levels between egg-eaters
and non-egg-eaters while there was a very significant difference between the
men who got exercise and those who didn’t.
A great many different steroids, each with a distinctive func¬tion 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 al¬cohols 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 150 °C and is insoluble in water but readily extracted from
tissues with chloroform, ether, benzene, or hot alcohol. Cholesterol occurs in
the plasma membranes of many animal cells and in the lipoproteins of blood
plasma. Lanosterol was first found in the waxy coating of wool in esterified
form before it was established as an important intermediate in the biosynthesis
of cholesterol in animal tissues.
Cholesterol is the precursor of many other steroids in animal tissues,
including the bile acids, detergentlike com¬pounds 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 com¬pounds 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 com¬ponents 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.
Phospholipids
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 hy¬droxyl groups are esterified to
fatty acids. The parent com¬pound of the series is thus the phosphoric ester of
glycerol.
Because phosphoglycerides possess a polar head in addi¬tion to their
nonpolar hydrocarbon tails, they are called amphipathic or polar lipids. The
dif¬ferent 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 phosphoglyc¬erides 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
phosphoglyc¬erides are major components of most animal cell mem¬branes.
In phosphqtidylserine, the hydroxyl group of the amino acid L-serine is
esterified to the phosphoric acid.
Closely related to phosphatidylglycerol is the more com¬plex 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 phospha¬tidic
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 abun¬dant.
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 3 g are taken by many people without adverse effects. The lipid soluble
vitamins, shown in the diagram below, are not as easily eliminated and may
accumulate to toxic levels if consumed in large quantity. The RDA for these
vitamins are:
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. 1 g)
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.
Properties of phosphoglycerides
Phosphoglycerides are solu¬ble in most nonpolar solvents containing some
water and are best extracted from cells and tissues with chloroform-methanol
mixtures. When phosphoglycerides are placed in water, they appear to dissolve,
but only very minute amounts go into true solution; most of the
"dissolved" lipid is in the form of micelles.
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. Re¬moval 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.
Sphingophospholipids
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
Sphingophospholipids, complex lipids containing as their backbone sphingosine,
are important membrane components in both plant and animal cells. They are
present in especially large amounts in brain and nerve tissue. Only trace
amounts of sphingophospholipids are found in depot fats. All
sphingophospholipids contain four characteristic building-block components: one
molecule of a fatty acid, one molecule of sphingosine, phosphoric acid and a
polar head group, which in some sphingolipids is very large and complex.
The most abundant sphingophospholipids in the tissues of higher animals are
sphingomyelins, which contain phosphorylethanolamine or phosphorylcholine as
their polar head groups, esterified to the 1-hydroxyl group of ceramide.
Sphingomyelins have physical properties very similar to those of
phosphatidylethanolamine and phosphatidylcholine.
Glycolipids
Glycosylglycerols
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
ver¬tebrates.
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-galac¬tose, 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 constit¬uents 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 im¬pulses 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 glycosphingo¬lipids
different from those in normal cells.
The most important derivatives of lipids
The lipids discussed up to this point contain fatty acids as building
blocks, which can be released on alkaline hydrol¬ysis. 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
biologi¬cal activity—vitamins, hormones, and other highly special¬ized
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.
Pros¬taglandins 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 ac¬tivity 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 com¬posed 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 mono¬glycerides
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 mole¬cules. 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 choles¬terol 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 monoglyc¬erides and fatty acids through
the brush border is based entirely on the fact that both these sub¬stances 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 mem¬brane of the
epithelial cell. However, only small quantities of these are normally absorbed
because the bile acid micelles will not dissolve either tri¬glycerides 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 choles¬terol 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 glob¬ules 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 chylomi¬crons.
Direct Absorption of fatty acids into the portal blood. Small
quantities of short chain fatty acids, such as those from butterfat, are
ab¬sorbed 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 triglyc¬erides
by the endoplasmic reticulum. This allows direct diffusion of these fatty acids
from the epi¬thelial cells into the capillary blood of the dlood.