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
(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:
2. Complex lipids:
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 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.
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.
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 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:
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 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.
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.
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.
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.
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.
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.
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.
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.
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.