Lipid Metabolism PDF

Nutrition andMetabolism Lipid Metabolism 02-Jul-22 Lipid Metabolism 1  Digestion and Absorption  Plasma lipids  Oxidation of fatty acids  Biosynthesis of fatty acids (Lipogenesis)  Triacylglycerol Metabolism  Ketone bodies Metabolism.  Cholesterol Metabolism 02-Ju...

Nutrition andMetabolism Lipid Metabolism 02-Jul-22 Lipid Metabolism 1  Digestion and Absorption  Plasma lipids  Oxidation of fatty acids  Biosynthesis of fatty acids (Lipogenesis)  Triacylglycerol Metabolism  Ketone bodies Metabolism.  Cholesterol Metabolism 02-Jul-22 Lipid Metabolism 2 Digestion and Absorption Adult human eats about 100 – 150-gram lipid per day. The main lipids in diet are triacylglycerols (TG) which constitute most of fat and oils we eat, but diet contains also some phospholipids and cholesterol. Pancreatic lipase is the most active and important for digestion of TG (activated by bile salts & calcium ions). Ingested TG are first emulsified in the stomach by gastric contraction, and in the intestine by bile salts.  Then under go enzymatic hydrolysis by lipase enzymes. Emulsification =breakdown of large fat into small ones. The digestion of TG starts in the small intestine. The emulsified TG are attacked by pancreatic lipase which hydrolyses the 1 &3 esters. The resulting 2-monoglyceride can be isomerised to 1 or 3 esters which can be hydrolyzed to form free glycerol. Thus the end products of digestion of TG are: 2 mono-acyl-glycerols + 1-mono-acyl-glycerols + glycerol, + saturated & unsaturated fatty acids. Absorption of lipids (TG): Short chain fatty acids (less than 12 C) and glycerols are water soluble, and pass via the portal system to the liver. Other lipids are water insoluble. They combine with bile salts to form a water-soluble complex called micelles, which enter the mucosal cells. Inside the intestine cells, the absorbed long chain fatty acids are re-esterified into TG.  These TG plus some cholesterol and phospholipids are bound to a protein to form chylomicron, which enter the circulation via lymphatic system at the thoracic duct. From the blood, the chylomicrons are taken by various tissue cells. Before entering these cells, the chylomicrons are hydrolyzed into fatty acids and glycerol by lipo-protein-lipase enzyme. Inside the tissue cells, these fatty acids are metabolized for energy or they are stored as TG.  Plasma Lipid Lipoprotein Structure, Function, and Metabolism 02-Jul-22 Lipid Metabolism 7 Plasma Lipoproteins Structure Lipids and specific proteins. LipoProtein core – Triglycerides – Cholesterol esters LipoProtein surface – Phospholipids – Proteins – cholesterol 02-Jul-22 Lipid Metabolism 8 PLASMA LIPOPROTEINS The lipoprotein include: Chylomicrons, very-low-density lipoproteins (VLDL), low-density lipoproteins (LDL), intermediate-density lipoproteins (IDL) and high-density lipoproteins (HDL). They differ in lipid and protein composition, size, and density. Lipoproteins function both to keep their component lipids soluble as they transport them in the plasma 02-Jul-22 Lipid Metabolism 9 Apo-lipoproteins functions  Recognition sites for cell-surface receptors.  serving as activators or coenzymes for enzymes involved in lipoprotein metabolism. Apolipoproteins are divided by structure and function into five major classes, A - E, with most classes having subclasses,EX, apoA-I and apo C-II 02-Ju l- 22 Lipid Metabolism 10  Plasma Lipoproteins Classes & Functions 1/ Chylomicrons  Synthesized in small intestine  Transport dietary TG, Cholesterol, cholesterol ester, fat-soluble vitamin, to the peripheral tissues.  98% lipid, large sized, lowest density.  Apo B-48: Receptor binding  Apo C-II: Lipoprotein lipase activator  Apo E: Remnant receptor binding in the liver 02-Jul-22 Lipid Metabolism 11 Plasma Lipoproteins Classes & Functions 02-Jul-22 Lipid Metabolism 12  Plasma Lipoproteins Classes & Functions Familial Chylomicronemia (type-1 hyperlipoproteinmia, or familial lipoprotein lipase deficiency) Is a rare disorder of lipoprotein metabolism due to familial lipoprotein lipase or apolipoprotein C-II deficiency, show a dramatic accumulation of chylomicrons in the plasma (hypertriacylglycerolemia).] 02-Jul-22 Lipid Metabolism 13  Plasma Lipoproteins Classes & Functions 2/ Very Low Density Lipoprotein (VLDL)  Synthesized in liver  Transport endogenous TG from liver to peripheral tissues  90% lipid, 10% protein  Apo B-100: Receptor binding  Apo C-II: LPL activator  Apo E: Remnant receptor binding 02-Jul-22 Lipid Metabolism 14  Plasma Lipoproteins Classes & Functions 3/ Intermediate Density Lipoprotein (IDL)  Synthesized from VLDL during VLDL degradation  Triglyceride transport and precursor to LDL  Apo B-100: Receptor binding  Apo C-II: LPL activator  Apo E: Receptor binding 02-Jul-22 Lipid Metabolism 15 02-Jul-22 Lipid Metabolism 16  Plasma Lipoproteins Classes & Functions 4/ Low Density Lipoprotein (LDL)  Synthesized from IDL  Transport cholesterol from liver to the peripheral tissues  Less TG, High cholesterol & CE  Apo B-100: Receptor binding. 02-Jul-22 Lipid Metabolism 17  Plasma Lipoproteins Classes & Functions Familial hypercholesterolemia A deficiency of functional LDL receptors causes a significant elevation in plasma LDL and, therefore, of plasma cholesterol. Patients with such deficiencies have type II hyperlipidemia. 02-Jul-22 Lipid Metabolism 18  Plasma Lipoproteins Classes & Functions 5/High Density Lipoprotein (HDL)  Synthesized in liver and intestine  Transport cholesterol from tissues to liver.  52% protein, 48% lipid, 35% C & CE  Apo A: Activates lecithin-cholesterol acyltransferase (LCAT)  Apo C: Activates LPL Apo E: Remnant receptor binding 02-Jul-22 Lip id Metabolism 19 Oxidation of fatty acids  Beta-oxidation The fatty acids that arrive at the surface of tissues are taken up by the cells and can be used fore energy production. During prolonged fasting most tissues are able to use fatty acids or ketone bodies for their energy requirements. The main pathway by which fatty acids are broken down. It is called the beta-oxidation because the carbon atom beta- to the carboxyl carbon is oxidized. Site Mitochondria. Because the mitochondrial inner membrane is impermeable to fatty acids, fatty acids react with carnitine to form acyl carnitine which can pass through the membrane. Importance of β-oxidation Source of energy Production of acetyl CoA. Ketone bodies formation.  Energetic of fatty acid oxidation: e.g. Palmitic acid (16 carbon). Beta-oxidation of palmitic acid will be repeated 7 times to produce 8 Acetyl-CoA. In each time, produced FADH2 and NADH+H.  8 Acetyl-CoA x 12 (TCA Cycle) = 96 ATP.  7 X (NADH+H + FADH2) 5 = 35 ATP  TOTAL = 131 ATP  Net: 131 ATP – 2ATP = 129 ATP Regulation of beta-oxidation:  Regulated by energy, when energy increases (ATP) inhibit E.T.C.  thus FADH2 & NADH+H can not under go oxidation in respiratory chain, lead to inhibition of beta-oxidation. Oxidation of fatty acids with odd number of carbon atoms  The oxidation of fatty acids with an odd number of carbon atoms proceeds exactly as described by the pathway of beta-oxidation,  but the final product is a molecule of propionyl CoA.  This compound undergoes carboxylation and conversion to succinyl CoA (C.A.C).  α-oxidation some fatty acids undergo α oxidation. This type of oxidation occurs in α-position and characterized by: It occurs in brain tissues. It is a minor pathway for fatty acid oxidation. There is one carbon atom removed At a time for α-position. w-oxidation w-oxidation gives rise to a dicarboxylic acid. Another minor pathway for fatty acid oxidation also involves hydroxylation and occurs in the endoplasmic reticulum of many tissues. In this case the hydroxylation takes place on the methyl carbon. The hydroxylated fatty acid can be further oxidized to a dicarboxylic acid. The process occurs primarily with medium chain fatty acids. CH3 – R – CH2 – CH2 – COOH + O2 HOOC – R – CH2 – CH2 – COOH+ H2  Biosynthesis of fatty acids (Lipogenesis) 02-Jul-22 Lipid Metabolism 29 Introduction:  Fatty acids can be derived from: breakdown of sugars, of some amino acids, and other fatty acids.  Palmitic acid, is first synthesized, and all other fatty acids are made by modification of palmitic acids.  Acetyl CoA is direct source of all carbon atoms for this synthesis.  The biosynthesis of fatty acid occurs depends on the amount of fat in the diet. 02-Jul-22 Lipid Metabolism 30  Biosynthesis of fatty acids Site of fatty acids synthesis: Intracellular in the cytosol. (Liver, kidney, brain, lung, mammary gland, adipose tissue). Building block:  Acetyl CoA (from glucose)  NADPH (from Pentose Phosphate Pathway)  ATP  Enzymes Regulation of fatty acid synthesis: Insulin: insulin stimulates Fatty acids synthesis through acetyl CoA Carbox y lase) 02-Jul-22 Lipid Me tab oli sm 31  Biosynthesis of fatty acids 02-Jul-22 Lipid Metabolism 32  Biosynthesis of fatty acids Steps of fatty acid synthesis: 02-Jul-22 Lipid Metabolism 33 Formation of palmitic acid: Butyryl-ACP (four-carbon unit) reacts with another malonyl group via the reaction described above, and the cycle continues. After seven turns of the cycle, palmitic –ACP is synthesized. Palmitic acid is released from the ACP and the fatty acid synthase complex by the enzyme palmitoyl deacylase. 02-Jul-22 Lipid Metabolism 34 Fate of palmitate: The free palmitate must be activated to palmityl CoA before it can proceed via any other pathway. (1) Esterification: Palmitate may under go esterification with glycerol or cholesterol. Palmitate + glycerol ====== acyl glycerol Palmitate+cholesterol == cholesterol ester (2) Chain elongation: Palmitate may be elongated to form fatty acids having a number of carbons more than 16. 02-Ju l-22 Lipid Metabolism 35 (3) Desaturation: Synthesis of unsaturated fatty acids. The two most common monounsaturated fatty acids in mammals are palmitoleic acid (16:1∆9) and oleic acid (18:1∆9). Stearic acid which is derived from elongation of palmitate may under go desaturation at C9 & C10 to form oleic acid. The double bonds are introduced between carbons 9 & 10 by fatty acid oxygenase 02-Jul-22 Lipid Metabolism 36 Regulation of fatty acid synthesis: The rate limiting reaction in the lipogenic pathway is the acetyl CoA carboxylase step. (1) Activators: (stimulates fatty acid synthesis through acetyl CoA Carboxylase) 1/ Citrate. 2/ Insulin: insulin stimulates transport of glucose into the cells and so it increases the availability of pyruvate === acetyl CoA === F.As synthesis. Also insulin inhibits lipolysis through the inhibition of cAMP this reduces the concentration of long chain acyl CoA which is an inhibitor of lipogenesis. 02-Jul-22 Lipid Metabolism 37 (2) Inhibitors: Long chain acyl CoA: Inhibits acetyl CoA carboxylase. due to excessive lipolysis or decreased esterification Inhibition of acetyl CoA carboxylase Lead to inhibition of synthesis of a new fatty acids. 02-Jul-22 Lipid Metabolism 38  Triacylglycerol Metabolism 02-Jul-22 Lipid Metabolism 39  Triacylglycerol Synthesis 1/ Fatty acids must be activated to Acyl-CoA Fatty acid +CoA + ATP Acyl-CoA synthetase Acyl-CoA + AMP + PPi 2/ Synthesis of glycerol phosphate: There are two ways for glycerol phosphate production: A/ liver and adipose tissue, glycerol phosphate can be produced from glucose, (from dihydroxyacetone phosphate). Next, DHAP is reduced by glycerol phosphate dehydrogenase to glycerol phosphate. 02-Jul-22 Lipid Metabolism 40  Triacylglycerol Synthesis B/ a second pathway found in the liver, but NOT in adipose tissue, uses glycerol kinase to convert free glycerol to glycerol phosphate 02-Jul-22 Lipid Metabolism 41  Triacylglycerol Synthesis Steps for Synthesis of TG from glycerol phosphate and fatty acylCoA Fatty acids stored in adipose tissue, in the form of TG, serve as the body's major fuel storage reserve. 02-Jul-22 Lipid Metabolism 42 02-Jul-22 Lipid Metabolism 43  Lipolysis (TG Degradation) Means breakdown of stored TG in adipose tissue into glycerol & F.F.A. The causes of excessive lipolysis occurs due to increased need TG for energy as in:  Starvation.  Uncontrolled diabetes mellitus.  Low carbohydrate diet. Lipolysis carried out by Hormone sensitive lipase enzyme. 02-Jul-22 Lipid Metabolism 44  Lipolysis (TG Degradation) Factors affecting lipolysis: (A) Factors stimulate lipolysis: 1/ Catacholamines (epinephrine & nor epinephrine). 2/ Glucagon 3/ Growth hormone. 4/ Thyroid stimulating hormone (TSH). 5/ Caffeine: it stimulate lipolysis through its inhibitory effect of the phosphodiestersae enzyme, thus keeping the already formed cAMP undestroyed. 02-Jul-22 Lipid Metabolism 45  Lipolysis (TG Degradation) Factors inhibit lipolysis: 1/ Insulin: by stimulating phosphodiesterase enzyme, leads to inactivation of hormone sensitive lipase. 2/ Nicotinic acid and prostaglandin E: both inhibit adenylate cyclase enzyme. 02-Jul-22 Lipid Metabolism 46  Ketone bodies Metabolism 02-Jul-22 Lipid Metabolism 47 Ketone bodies include:  Acetoacetic acid.  β-hydroxy butyric acid.  Acetone These substances used as energy for the, heart, skeletal muscle and kidney. Site of synthesis: liver from acetyl CoA. 02-Jul-22 Lipid Metabolism 48  Ketosis Ketone bodies after formed in the liver diffusion into blood. The production of ketone bodies equal utilization. Ketosis is a condition in which there is a high level of blood ketone bodies (Ketonemia) and a high level of urine ketone bodies (Ketonuria). Causes of ketosis: 1/ Starvation. 2/ Carbohydrate poor diet. 3/ Uncontrolled Diabetes mellitus. 02-Jul-22 Lipid Metabolism 49 02-Jul-22 Lipid Metabolism 50  Ketone bodies oxidation (ketolysis) Site: K.B oxidation occurs extra-hepatic tissue because liver dose not contain the enzymes responsible for this process (thiophorase), and acetoacetate thiokinase enzymes. Energy yield from oxidation of ketone bodies: Conversion of Beta-hydroxy-butyrate to acetoacetate yields NADH (3ATP). Each mole of acetyl CoAthat is formed yields 12 moleATPvia C.A.C. The activation reactions require 1 mole of ATP. Therefore, oxidation of acetoacetate yields 24 – 1 = 23 moleATP An oxidation of Beta-hydroxy-butyrate yields 24 + 3 – 1 = 26ATP. 02-Jul-22 Lipid Metabolism 51  Metabolism of Cholesterol 02-Jul-22 Lipid Metabolism 52 Sources: Endogenous: cholesterol is formed in the body in the liver from active acetate. Exogenous: Cholesterol is product of animal metabolism and occurs only in foods of animal origin. 02-Jul-22 Lipid Metabolism 53 Plasma cholesterol: Cholesterol present in plasma is either free or with fatty acid (cholesterol ester). Cholesterol transported in plasma in the form of lipoprotein: 60% is associated with LDL & 40% with HDL. Functions of cholesterol: 1/ Enter in the structure of every body cell. 2/ Precursor of vitamin D, bile salts & steroid hormones. 02-Jul-22 Lipid Metabolism 54 Synthesis of cholesterol: Site: the main site is the liver. Other tissues for cholesterol synthesis include:  Adrenal cortex: glucocorticoids  Skin: 7-dehdrocholesterol.  Testis: testosterone.  Intestine.  Ovary. Intracellular it occurs in cytoplasm. 02-Jul-22 Lipid Metabolism 55 Steps for cholesterol synthesis 02-Jul-22 Lipid Metabolism 56  Regulation of cholesterol biosynthesis  The key enzyme of cholesterol biosynthesis is HMG-CoA reductase.  The feeding of cholesterol reduces the hepatic biosynthesis of cholesterol by reducing the activity of HMG-CoAreductase.  HMG-CoA reductase activity is also reduced by fasting, which limits the availability of acetyl CoA and NADPH for cholesterol biosynthesis.  HMG-CoA reductase can undergo reversible phosphorylation- dephosphorylation the phosphorylated enzyme is less active than the dephosphorylated form. 02-Jul-22 Lipid Metabolism 57 02-Jul-22 Lipid Metabolism 58 Degradation of Cholesterol cholesterol nucleus is eliminated from the body by conversion to bile acids and bile salts, which are excreted in the feces, Some of the cholesterol in the intestine is modified by bacteria before excretion to coprostanol and cholestanol, which are reduced derivatives of cholesterol. 02-Jul-22 Lipid Metabolism 59