Lipid Metabolism_Tanvimadam PDF

What are lipids ? Lipids are heterogeneous groups of compounds related either directly or indirectly to fatty acids. They are insoluble in water and soluble in fat solvents such as alcohol and ether. Functions Of Lipids 1. Lipids are the constituents of cell membrane and regulate...

What are lipids ? Lipids are heterogeneous groups of compounds related either directly or indirectly to fatty acids. They are insoluble in water and soluble in fat solvents such as alcohol and ether. Functions Of Lipids 1. Lipids are the constituents of cell membrane and regulate membrane permeability. 2. Lipids protect internal organs, serve as insulating materials and give shape and smoothness to the body. 3. Lipids serve as a source of fat soluble vitamins. 4. Essential fatty acids are useful for transport of cholesterol, formation of lipoproteins, etc. 5. Phospholipids in mitochondria are responsible for transport of electron transport chain components. 6. Accumulation of fat in liver is prevented by phospholipids. 7. Phospholipids help in removal of cholesterol from the body by participating in reverse cholesterol transport. 8. Cholesterol (sterol of animals) is a constituent of membrane structure and it synthesizes bile acids, hormones and vitamin D. Oxidation of fatty acids  BETA OXIDATION OF FATTY ACIDS This process is known as beta oxidation, because oxidation and splitting of two carbon units occur at the beta-carbon atom. The oxidation of hydrocarbon chain occurs by a sequential cleavage of two carbon atoms. Preparative Steps for Beta Oxidation The co-enzyme A is a complex molecule containing B complex vitamin pantothenic acid and a molecule of beta mercapto ethanolamine; this SH group forms thioester bond in acyl CoA. To emphasise function of SH group, CoA is sometimes written as CoA-SH.  Preparative Step 1: Activation of Fatty Acids  Fatty acids are activated to their co-enzyme A (CoA) derivative. This activation is taking place in cytoplasm. ATP is hydrolysed to AMP and PPi and energy from hydrolysis of PPi drives reaction forward. Thus two high energy bonds are utilised in this reaction. The enzyme is a thiokinase or fatty acyl CoA synthetase (step 0). Acetyl group and acyl groups are diferent. Three diferent enzymes, one each for short chain, medium chain and long chain fatty acids have been identifed. Small chain fatty acids may also be activated by thiophorase enzyme, using succinyl CoA (see under ketone bodies).  Preparative Step 2: Role of Carnitine Fatty acids are activated in the cytoplasm; but the beta oxidation is in mitochondria. So transport of fatty acids through mitochondrial membrane is essential. The long chain fatty acyl CoA cannot pass through inner mitochondrial membrane. Therefore a transporter, carnitine is involved in transfer of fatty acids. Carnitine is beta-hydroxygamma- trimethyl ammonium butyrate. It is synthesised from lysine and methionine in liver and kidney. Preparative Step 3: Carnitine Acyl Transferase  The enzyme carnitine acyl transferase-I (CAT-I) will transfer the fatty acyl group to the hydroxyl group of carnitine to form acyl carnitine.  The reaction occurs on cytosolic side of inner mitochondrial membrane. Role of carnitine in transport of acyl groups. CAT = Carnitine acyl transferase Preparative Step 4: Translocase  A protein translocase will carry the acyl carnitine across membrane to the matrix of mitochondria. On the matrix side of membrane another enzyme, carnitine acyl transferase-II (CAT- II) will transfer the acyl group back to co- enzyme A molecule. Carnitine is returned to cytosolic side by the translocase. Beta Oxidation Steps  The next 4 reactions are sequentially repeated for complete oxidation of fatty acids. After one round of four metabolic steps, one acetyl CoA unit is split of and acyl CoA with 2 carbon atoms less is generated. This would undergo same series of reactions again until fatty acid is completely oxidised. Step 1: FAD Linked Dehydrogenase The fatty acyl CoA is dehydrogenated to a trans enoyl CoA with FAD accepting the hydrogen atoms (step 1).  FADH2 when oxidised in electron transport chain will produce 1.5 ATP molecules. Step 2: Hydration This is catalysed by an enoyl CoA hydratase (step 2). This step forms a beta-hydroxy fatty acyl CoA.  The L isomer alone is formed during hydration of the trans double bond. Step 3: NAD+ Dependent Dehydrogenase  The beta-hydroxy fatty acyl CoA is again oxidised to form beta-keto fatty acyl CoA (step 3).  This dehydrogenase acts only on L isomer.  The NADH when oxidised in electron transport chain will generate 2.5 ATPs. Step 4: Cleavage  The beta-keto fatty acyl CoA now undergoes thiolytic cleavage, splitting of a molecule of acetyl CoA and leaving behind a fatty acid with 2 carbon atoms less (step 4). Further Cycles  The newly formed fatty acyl CoA will sequentially undergo further cycles of steps 1, 2, 3 and 4 of beta- oxidation until the fatty acid is completely converted to acetyl CoA. Energetics of Beta Oxidation (ATP Yield)  Palmitic acid (16 C) needs 7 cycles of beta oxidation.  So, it gives rise to 8 molecules of acetyl CoA.  Every molecule of acetyl CoA when oxidised in the TCA cycle gives 10 molecules of ATP.  Each molecule of FADH2 produces 1.5 molecules of ATP and each NADH generates 2.5 molecules of ATP, when oxidised in the electron transport chain.  According to new concept,  Hence energy yield from one molecule of palmitate may be calculated as: 8 acetyl CoA × 10 = 80 ATP 7 FADH2 × 1.5 = 10.5 ATP 7 NADH × 2.5 = 17.5 ATP Gross total = 108 ATP Net yield = 108–2 = 106 ATP  According to old concept, Summary of beta NADH produces 3 ATPs and oxidation of palmitic FADH generates 2 ATPs. This acid (16 C). It will amount to a net undergoes 7 cycles, which give rise to 8 generation of 129 ATP per molecules of acetyl CoA palmitate molecule. Lipoproteins: VLDL, HDL and their importance  Lipoproteins are molecular complexes of lipids with proteins. They are the transport vehicles for lipids in the circulation. There are fve types of lipoproteins. 1. Chylomicrons 2. Very low density lipoproteins (VLDL) 3. Low density lipoproteins (LDL) 4. High density lipoproteins (HDL) 5. Free fatty acid albumin complexes 1. Chylomicrons : They are synthesized in intestine and transport exogenous (dietary) triacylglycerol to various tissues.  They consist of highest (99%) quantity of lipid and lowest (1%) concentration of protein. The chylomicrons are least in density and the largest in size, among lipoproteins. 2. Very low density lipoproteins (VLDL) : They are produced in liver and intestine and are responsible for transport of endogenously synthesized triacylglycerols. 3. Low density lipoproteins (LDL) : They are formed from VLDL in the blood circulation. They transport cholesterol from liver to other tissues. 4. High density lipoproteins (HDL) :  They are mostly synthesized in liver. Three diferent fractions of HDL (1, 2 and 3) can be identifed by ultracentrifugation.  HDL particles transport cholesterol from peripheral tissues to liver (reverse cholesterol transport). 5. Free fatty acids—albumin :  Free fatty acids in the circulation are in a bound form to albumin.  Each molecule of albumin can hold about 20-30 molecules of free fatty acids. This lipoprotein cannot be separated by electrophoresis. Apolipoproteins (apoproteins) The protein components of lipoproteins are known as apolipoproteins or, simply, apoproteins. They perform the following functions 1. Act as structural components of lipoproteins. 2. Recognize the cell membrane surface receptors. 3. Activate enzymes involved in lipoprotein metabolism. The various types of lipoproteins have diferent functions Chylomicrons and VLDLs:  Chylomicrons and VLDLs are the principal carriers of triglycerides and Choleterols in blood. The concentrations are increased in atheroscorosis and coronary thrombosis. LDLs: In LDLs the predominant lipid is cholesterol and phospholipids. Increased in atherosclerosis and coronary thrombosis, etc.  HDLs: HDLs are predominant lipid is phospholipid and proteins. LDLs and HDLs are involved in the cholesterol transport. LDLs carry about 80% of cholesterol while the remaining is carried by HDLs.  LDLs carry cholesterols to cells for their use where as HDLs carry excess cholesterol away from the cells to the liver for processing and excretion from the body. The levels of LDL correlate directly with heart disease, where as HDL levels correlates inversely with heart disease risk.  Thus HDL is some times referred to as “good” cholesterol and LDL as “bad” cholesterol. Thank you