Lipids PDF

Lipids Lipids (Greek: lipos = fat) are substances of biological origin that are insoluble or sparingly soluble in water but are generally soluble in organic solvents such as methanol and chloroform Hence, they are easily separated from other biological materials by extraction into orga...

Lipids Lipids (Greek: lipos = fat) are substances of biological origin that are insoluble or sparingly soluble in water but are generally soluble in organic solvents such as methanol and chloroform Hence, they are easily separated from other biological materials by extraction into organic solvents Fats, oils, certain hormones and vitamins and some components of plasma membrane are lipids. Fatty Acids Fatty acids are carboxylic acids with long-chain hydrocarbon side groups They are rarely free in nature, but rather, occur in esterified form as a major components of the various lipids. In higher plants and animals, the predominant fatty acid residue are those with 16 and 18 carbons (palmitic, oleic, linoleic, and stearic acids) Fatty acids with less than 14 or greater than 20 carbon atoms are not very common  Most fatty acids have an even number of carbon atoms because they are usually biosynthesized by the concatenation of 2-C units More than 50% of the fatty acid residue in plant and anima lipids are unsaturated (contain double bonds) and most times polyunsaturated Physical Properties of Fatty Acids The double bond of an unsaturated fatty acid commonly occurs between C-9 and C-10 (∆9) In polyunsaturated Fas, the double bonds tend to occur at every third carbon atom toward the methyl terminus of the molecule (-CH=CH-CH2-CH=CH-) The double bonds in polyunsaturated Fas are almost never conjugated (as in -CH=CH-CH=CH-) Triple bonds rarely occur in FAs Saturated Fas are highly flexible molecules that can assume a wide range of conformations because there is relatively free rotation about each of their C-C bonds  The melting points of saturated FAs, increase with molecular mass Double bonds of FA almost always have the cis configuration This put a rigid 30° bend in the hydrocarbon chain of unsaturated FAs that interferes with their efficient packing to fill space Consequently, the reduced van der Waals interactions cause FA melting points to decrease with their degree of unsaturation Lipid fluidity likewise increases with the degree of unsaturation of their component FA residues Triacylglycerol The fats and oils that occur in plants and animals consist largely of mixture of triacylglycerol (TG) also referred to as triglycerides or neutral fats TGs are nonpolar triesters of glycerol TGs majorly function as energy reservoirs in animals and are therefore the most abundant class of lipids in animals TGs differ according to the identity and placement of their 3 fatty acid residues Simple TGs contain one type of FA residue e.g. trioleoylglycerol or triolein has 3 oleic acid residues Mixed TGs contain 2 or 3 different types of Fas residues and are named according to their placement on the glycerol moiety Phospholipids There are 2 classes of phospholipids namely; 1. Those that have glycerol as a backbone (glycerolphospholipids or phosphoglycerides) and, 2. Those that contain sphingosine as a backbone (shingophospholipids) Glycerophospholipids Glycerophospholipids are the major lipid components of biological membranes. Glycerophospholipids are derivative of phosphatidic acids (diacylglycerol + phosphate group on the 3rd carbon).  Phosphatidic acid is the simplest phosphoglycerides and is the precursor of the other members of this group Other phosphoglycerides are formed from phosphatidic acid (PA) and an alcohol That is, the PA can be esterified to another compound containing an alcohol group For instance: 1. PA + Serine = phosphatidylserine 2. PA + ethanolamine = phosphatidylethanolamine (cephalin) 3. PA + choline = phosphatidylcholine (lecithin) 4. PA + inositol = phosphatidylinositol 5. PA + glycerol = phosphatidylglycerol Shingophospholipids: sphingomyelin The backbone of shingophospholipids is the amino alcohol sphingosine, rather than glycerol. A long-chain FA is attached to the amino group of sphingosine through an amide linkage producing a ceramide which can also serve as a precursor of glycolipids The alcohol grouo of C! of sphingosine is esterified to phosphorylcholine producing sphingomyelin, the only significant shingophospholipids in humans Shingomyelin is an important constituent of the myelin of nerve fibres Lipoproteins Lipids that are absorbed from the diet and synthesized by the liver and adipose tissue must be transported between various cells and organs for effective utilization and storage Lipids, unlike other macromolecules, are insoluble in water The problem of transportation of lipids in the aqueous plasma (blood) is solved by associating non-polar lipid (triacylglycerol and cholesteryl esters) with amphipathic lipids (phospholipids and cholesterol) and proteins to form water- miscible lipoproteins  The plasma lipoproteins are spherical macromolecular complexes of lipids and proteins Lipoprotein consist of a nonpolar core and a single surface layer of amphipathic lipids The nonpolar core consists of mainly triacylglycerol and cholesteryl ester The nonpolar core is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules The structure are oriented in a such a way that the polar groups face outward to the aqueous medium The protein moiety of a lipoprotein is known as an apolipoprotein or apoprotein. Classification of Lipoproteins The 4 lipoprotein particles differ in: 1. Density. 2. Size, 3. Lipid and protein composition, and 4. Site of origin Based on density, there are 4 lipoprotein particles: 1. Chylomicrons, 2. Very-low-density lipoproteins (VLDL), 3. Low-density lipoproteins (LDL), and 4. High-density lipoproteins (HDL).  Based on size and density of lipoprotein particles, chylomicrons are the lipoprotein particles lowest in density and largest in size It contain the highest percentage of lipid and lowest percentage of protein VLDLs and LDLs are successively denser, having higher ratios of protein to lipid HDL particles have the highest density Chylomicrons: they are derived from intestinal absorption of triacylglycerol and other lipids The density is generally is than 0.95 while the mean average diameter is between 100-500 nm  VLDLs: they are derived from the liver for the proper export of triacylglycerol The density lies between 0.95-1.006 and the mean diameter lies between 30-80 nm LDLs: it represent the final stage in the catabolism of VLDL The density lies between 1.019-1.063 and mean diameter is between 18-28 nm HDLs: it is involved in the transport of cholesterol It is also involved in the metabolism of chylomicron and VLDL The density ranges from 1.063-1.121 and the mean diameter is 5.15 nm.  Chylomicrons are assembled in the intestestinal mucosal cells and carry dietary triacylglycerol, cholesterol, fat soluble vitamins, and cholesteryl esters to the peripheral tissues VLDLs are produced in the liver they are composed predominantly of triacylglycerol and they function to carry triacylglycerol from the liver to the peripheral tissues In the peripheral tissues, the triacylglycerol is degraded by lipoprotein lipase Fatty liver (hepatic steatosis) occurs in conditions in which there is imbalance between hepatic triacylglycerol synthesis and the secretion of VLDL Such conditions include obesity, uncontrolled diabetes mellitus, and chronic ethanol ingestion  LDLs contain much less triacylglycerol than their VLDL predecessors, and have high concentration of cholesteryl esters The primary function of LDL particles is to provide cholesterol to the peripheral tissues or return it to the liver HDL comprise a heterogeneous family of lipoproteins with a complex metabolism that is not yet understood HDLs are synthesize and secreted from both the liver and intestine The major function of HDL is to act as a repository for the apo C and apo E required in the metabolism of chylomicrons and VLDL  HDL also scavenge extra cholesterol from peripheral tissues by reverse cholesterol transport HDL competes with LDL for binding sites on the membrane and prevents internalization of LDL cholesterol in the smooth cells of the arterial walls Reverse cholesterol transport The selective transfer of cholesterol from peripheral cells to HDL, and from HDL to the liver for bile acid synthesis, or disposal via the bile, and to steroidogenic cells for hormone synthesis is a key component of cholesterol homeostasis This is, in part, the basis for the inverse relationship seen between HDL concentration and atherosclerosis, and for HDL’s designation as the “good” cholesterol carrier  Reverse cholesterol transport involves: 1. Efflux of cholesterol from peripheral cells to HDL, 2. Esterification by phosphatidylcholine cholesterol transferase (PCAT), 3. Binding of the cholesteryl ester-rich HDL (HDL2) to liver and steroidogenic cells, 4. The selective transfer of the cholesteryl esters into these cells, and 5. The release of lipid-depleted HDL (HDL3)  Metabolism of lipid About 90% of the dietary lipid occur as triacylglycerol (fats). Triacylglycerol (TG) is the major form of metabolic energy storage in humans. Recall that TG consist of glycerol trimesters of fatty acids 26  Since carbon atoms of TG have lower oxidation state than those of glucose, the oxidative metabolism of fats yields over twice the energy of an equal weight of dry carbohydrate or protein Meanwhile, fats being nonpolar are stored in an anhydrous (containing no water) state. This is unlike glycogen (the storage form of glucose), which is polar and store in a hydrated form that contains about twice its dry weight of water. Fats therefore provide up to six times the metabolic energy of an equal weight of hydrated glycogen. 27  Digestion of lipid TGs are insoluble in water, whereas digestive enzymes are water soluble, digestion of lipids therefore take place at lipid-water interfaces The rate of TG digestion therefore depends on the surface area of the interface. The surface are of the interface is enhanced by the churning peristaltic movements of the intestine and the emulsification by bile salts The bile salts is a very powerful digestive detergents that are synthesized by the liver and secreted by the gall bladder into the small intestine where lipid digestion and absorption take place mainly. Pancreatic lipase catalyzes the hydrolysis of TG at its positions 3, and 1 to form 1,2-diacylglycerol and 2-acylglycerol respectively together with Na+ and K+ salts of the fatty acids (soaps). Since these soaps are amphipathic, they also aid the emulsification process 28  The mixture of fatty acids, mono- and diacylglycerol produced by lipid digestion is absorbed by the cells lining the small intestine (intestinal mucosa) facilitated by bile salts. The micelles formed by the bile salts take up the nonpolar lipid degradation products so as to permit their transport across the intestinal wall. Bile salts therefore, are not only facilitate lipid digestion, but are essential for the absorption of lipid digestion products and lipid-soluble vitamins. The lipid digestion products absorbed by the intestinal mucosa are converted by these tissues to TGs and then packaged into lipoprotein particles known as chylomicrons. The chylomicrons are in turn released into the bloodstream through the lymph system for delivery to the tissues. Similarly, TG synthesized by the liver are packaged into very low density lipoproteins (VLDL) and are released directly into the blood. 29  The TG components of chylomicrons and VLDL are hydrolyzed to free fatty acids (FFAs) and glycerol in the capillaries of adipose tissue and skeletal muscle by lipoprotein lipase. The resulting FFAs are taken up by these tissues, while the glycerol is transported to the liver or kidneys. In the liver and the kidneys, the glycerol is converted to dihydroxyacetone phosphate (an intermediate of the glycolytic pathway) by the sequential action of glycerol kinase and glycerol-3-phosphate dehydrogenase. Mobilization of TGs stored in the adipose tissue also involves their hydrolysis to glycerol and FFAs by the hormone-sensitive triacylglycerol lipase. The FFAs are thereafter released into the bloodstream, where they bind to serum albumin. 30  Fatty acid oxidation Before Fas can be oxidized, they must be activated in an ATP-dependent acylation reaction to form fatty acyl-CoA This activation process is catalyzed by a family of at least 3 acyl-CoA synthetases (thiokinase) FA + CoA + ATP acyl-CoA + AMP + PPi 31  Transport across the Mitochondrial Membrane Although FAs are activated for oxidation in the cytosol, they are oxidized in the mitochondrion. The activated FA (fatty acyl-CoA) must therefore be transported across the inner mitochondrial membrane. A long-chain fatty acyl-CoA cannot directly cross the inner mitochondrial membrane. Rather, its acyl portion is first transferred to carnitine ((CH3)3N+ - CH2 – CHOH – CH2 – COO-) - 4-trimethylamino-3-hydroxybutyrate 32 33 1. The acyl group of a cytosolic acyl-CoA is transferred to carnitine, thereby releasing the CoA to is cytosolic pool. 2. The resulting acyl-carnitine is transported into the mitochondrial matrix by the transport system (a specific carrier protein). 3. The acyl group is transferred to a CoA molecule from the mitochondrial pool. 4. The product carnitine is returned to the cytosol. The cell thereby maintains separate cytosolic and mitochondrial pools of CoA 34  β Oxidation 35 Fas are oxidized via the β oxidation, a 4 reactions pathway: 1. Formation of a trans-α,β double bond through dehydrogenation by acyl- CoA dehydrogenase 2. Hydration of the double bond by enoyl-CoA hydratase to form 3- hydroxyacyl-CoA 3. NAD+-dependent dehydrogenation of the β-hydroxyacyl-CoA by 3- hydroxyacyl-CoA dehydrogenase to form the corresponding β-ketoacyl- CoA 4. Cα - Cβ cleavage in a thiolysis reaction with CoA as catalyzed by β- ketoacyl-CoA thiolase (thiolase) to form acetyl-CoA and a new acyl-CoA containing 2 less C atoms than the original one. 36  Ketone Bodies Acetyl-CoA produced by β oxidation can be further oxidized via the TCA cycle A significant fraction of the acetyl-CoA has another fate apart fro TCA cycle. They are further metabolized through a process that is known as ketogenesis The process occur primarily in the hepatocyte mitochondrial In ketogenesis, acetyl-CoA is converted to acetoacetate or β- hydroxybutyrate 37  These 2 compounds together with acetone are referred to as ketone bodies They are water-soluble equivalents of fatty acids 38  Ketogenesis 39 1. Two molecules of acetyl-CoA are condensed to acetoacetate by a thiolase enzyme. 2. Condensation of the acetoacetate with a third acetyl-CoA b y HMG-CoA synthase to form β-hydroxyl-β-methylglutaryl-CoA (HMG-CoA). 3. Degradation of HMG-CoA to acetoacetate and acetyl-CoA catalyzed by HMG-CoA lyase. The overall reaction catalyzed by HMG-CoA synthase and HMG-CoA lyase is: Acetoacetyl-CoA + H2O acetoacetate + CoA 40  Ketone bodies serve as metabolic fuels for many peripheral tissues, most especially, heart and skeletal muscle. The brain under normal condition, uses glucose as its sole source of energy. Meanwhile FAs cannot pass through the blood-brain-barrier. During starvation however, ketone bodies become the major source of fuel for the brain 41  Acetoacetate, being a β-keto acid also undergo decarboxylation to acetone and CO2 The breath of individual with ketosis (ketoacidosis), a pathological conditions in which acetoacetate is produced faster than it can be metabolized (a symptom of diabetes) has the characteristic sweet smell of acetone. The liver releases acetoacetate and β-hydroxybutyrate into the circulation and are transported to the peripheral tissues for use as an alternative fuels. 42 Cholesterol Cholesterol is a very hydrophobic compound It consists of 4 fused rings; A, B, C, and D called the steroid nucleus It also has an 8-carbon, branched hydrocarbon chain attached to C-17 of the D ring Ring A has a hydroxyl group at C-3 Ring B has a double bond between C-5 and C-6 Structure of Cholesterol Functions of Cholesterol 1. Cholesterol is the structural component of all cell membranes, where it modulate the fluidity of the cell membrane, 2. In specialize tissues, cholesterol is the precursor of bile acids, steroid hormones and vitamin D The liver plays a central role in the regulation of the body’s cholesterol homeostasis In humans, the balance between cholesterol influx and efflux is not precise, resulting in a gradual deposition of cholesterol in the tissues, particularly, in the endothelia linings of blood vessels.  This is a potentially life-threatening occurrence when lipid deposition leads to plaque formation, causing the narrowing of the blood vessels (atherosclerosis) and increased risk of coronary artery disease  Cholesterol Metabolism Cholesterol is an important constituents of cell membranes and is also the precursor of steroid hormones and bile salts. Cholesterol is essential to life, yet its deposition in arteries has been associated with cardiovascular disease and stroke. In healthy individual, a balance is maintained between cholesterol biosynthesis, utilization, and transport, ensuring that deposition in the arteries is kept to a minimal level. Cholesterol is not essential in human diets, because all cells can synthesize it from simple precursors 47  Cholesterol Biosynthesis. Cholesterol is a 27-carbon compound suggesting a complex biosynthetic process. All the carbon atoms of cholesterol are derived from acetate. The pathway of cholesterol biosynthesis can be summarized as follow: 48 1. Synthesis of mevalonate from acetate The is the first stage in the cholesterol biosynthetic pathway, in this stage, 2 molecules of acetyl-CoA condensed to form acetoacytyl-CoA catalyzed by thiolase. This in turn condensed with the third acetyl-CoA to form HMG-CoA catalyzed by HMG-CoA synthase. In the third reaction, HMG-CoA reductase reduced HMG-CoA to mevalonate. NADPH is the reducing equivalent. This is the rate limiting and committed step of cholesterol biosynthesis. 49 2. Conversion of Mevalonate to 2 activated Isoprenes In this stage, 3 phosphate groups are transferred from 3 ATP molecules to mevalonate to form an intermediate known as 3-phosphate-5- pyrophosphomevalonate. In the next step, 3-phosphate-5-pyrophosphomevalonate is converted to ∆3- isopentenyl pyrophosphate – the first of the 2 isoprenes. Isomerization of ∆3-isopentenyl pyrophosphate yields the second activated isoprene refer to as dimethylallyl pyrophosphate 50 3. Condensation of 6 activated Isoprene Units to form Squalene In this stage, ∆3-isopentenylpyrophosphate and dimethylallyl pyrophosphate undergo a head-to-tail condensation reaction. In this condensation reaction, one pyrophosphate group is displaced and a 10-carbon chain geranyl pyrophosphate is formed. In the next step, geranyl pyrophosphate undergo another head-to-tail condensation reaction with ∆3-isopentenylpyrophosphate to form a 15- carbon intermediate, farnesyl pyrophosphate. In the final step of this stage, 2 molecules farnesyl pyrophosphate join head- to-head with concomitant loss of bothe pyrophosphate groups yielding squalene, 51 4. Conversion of Squalene to the 4-Ring Steroid Nucleus The first step in this stage is catalyzed by squalene monooxygenase for which NADPH is a co-substrate. The product is an epoxide, which in next step is cyclized to the steroid nucleus. 52  Utilization of Cholesterol Cholesterol is the precursor of steroid hormones and bile salts. Steroids hormones (progestins, glucocorticoids, mineralocorticoids, androgens and estrogens) mediate a wide variety of important physiological functions. The quantitatively most important pathway for cholesterol excretion in human is the formation of bile salts (the conjugate bases of bile acids) The major bile salts are cholate and chenodeoxycholate. They are synthesized in the liver and secreted as glycine or taurine conjugates into the gallbladder. 53  From the gallbladder, they are secreted into the small intestine, where they act as emulsifying agents in the digestion and absorption of fats and fat- soluble vitamins. An effective recycle system allow bile salts to reenter the bloodstream and return to the liver for reuse several times each day Small amount of bile salts normally escape this recycling process and are further metabolized by microorganisms in the large intestine and are excreted. This is the body’s only route for cholesterol excretion. 54 Degradation of Cholesterol The ring of cholesterol cannot be metabolized to CO2 and H2O in humans Instead, the intact cholesterol nucleus is eliminated from the body by conversion to bile acids and bile salts, which are excreted in the feces, and by secretion of cholesterol to bile Bile is transported in the intestine for elimination Some of the cholesterol in the intestine is modified by bacteria before excretion The primary compounds made are the isomers of coprostanol, which are reduced derivatives of cholesterol Isomers of coprostanol, together with cholesterol, make up the neutral fecal sterols