Overview of Lipid Metabolism

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1 Overview of Lipid Metabolism Learning Objectives By the end of this lecture the students should be able to understand: Classification of Lipids The digestion, absorption and utilization of dietary lipids Lipogenesis and Lipolysis Lipid malabsorption The functions of cholesterol Cholesterol synthesis and metabolism Cholesterol transport Classification of lipids Fatty Acids Fatty acids are long chain carboxylic acids having a terminal carboxyl (COOH-) group Saturated Fatty Acids: have no double bonds e.g. Palmitic acid and Stearic acid Unsaturated Fatty Acids: have one or more double bonds Essential Fatty Acids Fatty Acids that can not be synthesized de novo and have to supplied in the diet Linoleic acid Linolenic acid Triglycerides When one, two or three fatty acids are esterified to a molecule of glycerol; they form mono, di or triacylglycerols aka TGs Lipids are stored within adipose tissue as fat droplets made up of TGs Lipogenesis Lipid synthesis: From glycerol derived from Dihydroxyacetone phosphate from glycolysis Occurs in the liver and to a small extent in adipose tissue

2 Acetyl coa can form any fatty acid except for the essential FA The main rate limiting enzyme of lipid synthesis is Fatty Acid Synthase Lipolysis Lipid catabolism where lipids become: Glycerol Free fatty acids Glycerol can be converted to pyruvic acid which enters TCA Fatty Acids are degraded by beta oxidation, occurs in mitochondria of liver, muscle and adipose tissue The Dietary Lipids An adult consumes about g of lipid per day Much of it is composed of Triglycerides Remaining is made up of free Fatty acids, Cholesterol, cholesterol esters and phospholipids Digestion of Dietary Lipids Digestion begins in the GIT with the action of Lipase Gastric lipase requires neutral ph to emulsify fat In adults much of the dietary lipids are transported unchanged to the small intestine owing to acidic ph of the stomach Emulsification of Dietary Lipids In the small intestine the pancreatic secretions digest the dietary lipids Bile Salts emulsify fat droplets Pancreatic lipase digests triglycerides into monoglycerides and free fatty acids Pancreatic cholesterol esterase digests CE into cholesterol and FFA Absorption of lipids across intestinal mucosa FFA, cholesterol and monoacylglycrol together with bile salts, constitute micelles to get absorbed across the intestinal mucosal cells

3 Micelles: amphipathic structures with hydrophobic core containing the water insoluble lipids, and hydrophilic outer shell soluble in aqueous medium of intestinal epithelium Lipid transport from intestinal mucosa Once inside the intestinal mucosal cells, the absorbed lipids are resynthesized into TG and CE ( cholesterol esters ) Intestinal cells synthesize apolipoprotein B-48 and package TG and CE into Chylomicrons Chylomicrons are secreted first into the lymphatics and then into the blood Lipoproteins TGs and Cholesterol are transported in blood as Lipoproteins. According to density the lipoproteins are classified as Chylomicrons VLDL (very low density lipoproteins ) IDL (intermediate density lipoproteins ) LDL (low density lipoproteins ) HDL (high density lipoproteins ) Classes of lipoproteins with associated Apoproteins Lipoprotein Function Apoprotein Chylomicrons Transport dietary TG and CE from intestine to tissues apob-48 apoc-ii apoe VLDL Transport TG from liver to tissues apob-48 apoc-ii apoe LDL Delivers cholesterol into cells apob-100 IDL Picks up cholesterol from HDL to become LDL Picked up by liver apoe HDL Picks up cholesterol accumulating in blood vessels apoa1 Lipoproteins and their functions

4 Complex lipids Phospholipids Polar, amphipathic, ionic compounds composed of alcohol attached to a diacylglycerol or sphingosine Phosphoglycerides Phospholipids containing glycerol Sphingomylin Phospholipids containing sphingosine Fatty acid + sphingosine = Ceramide Glycolipids Derivatives of ceramide Components of cell membranes Serve as receptors of certain bacterial and viral toxins Antigenic: tumor antigens, embryonal antigens and sources of blood group antigens Cholesterol Component of cell membranes Steroid synthesis Precursor of steroid hormones e.g. corticosteroids, aldosterone, estrogen and testosterone Vitamin D precursor bile acid precursor Fat malabsorption Syndrome of fat malabsorption consists of Diarrhea, steatorria, malabsorption, wasting and vitamin deficiencies Some common causes are: Lactase deficiecy Celiac sprue Pernicious anemia

5 Blind loop syndrome Lymphatic obstruction Tuberculosis lymphoma Deficiencies in Fat malabsorption Deficiency of Fat soluble vitamins: vitamin A, D, E and K Iron deficiency-anemia Vitamin B12/ Folate deficiency- Megaloblastic anemia Vitamin K deficiency- easy bruising Vitamin D deficiency- osteopenia Cholesterol Metabolism and CVS Function Cholesterol The major sterol compose of four fused rings and an eight-membered, branched hydrocarbon chain

6 Functions of Cholesterol Necessary part of cell membranes Precursor molecule for steroid synthesis Aldosterone Corticosteroids Estrogens Progesterone Testosterone Bile acid for digestion Vitamin D Sources of Cholesterol

7 Cholesterol Synthesis Occurs in cytosol Requires NADPH and ATP Highly regulated 80 % in liver, ~10% intestine, ~5% skin Hydroxymethylglutaryl-coenzyme A (HMG-CoA) is the precursor for cholesterol synthesis. HMG-CoA is also an intermediate on the pathway for synthesis of ketone bodies from acetyl-coa.

8 Formation of HMG CoA-Rate Limiting step HMG-CoA is formed by condensation of acetyl-coa & acetoacetyl- CoA, catalyzed by HMG-CoA Synthase. HMG-CoA Reductase catalyzes production of mevalonate from HMG- CoA H 2 O O H 3 C C CH 2 C SCoA acetoacetyl-coa H 3 C C SCoA acetyl-coa HMG-CoA HSCoA Synthase O O O OH O O C CH 2 C CH 2 C SCoA CH 3 hydroxymethylglutaryl-coa

9 Regulation of Cholesterol Synthesis Cholesterol Transport Chylomicrons: Chylomicrons transport triglycerides from intestine Very Low Density Lipoproteins (VLDL) and Intermediate Density Lipoproteins (IDL) : VLDL produced in liver. Carry cholesterol and triglycerides Low Density Lipoproteins (LDL) LDL result from metabolism of VLDL and IDL and carry cholesterol. LDL are important cause of heart disease High Density Lipoproteins(HDL) HDL is good cholesterol. It removes cholesterol and protects against heart disease

10 Cholesterol Transport Hypercholestrolemia Blood Cholesterol levels Total cholesterol < 5.17 mmol/l = Good = Borderline High

11 > 6.20 = High LDL < 2.58 mmol/l = Good = Near Normal = Borderline High = High > 4.88 = Very High Hypercholestrolemia

12 Hypercholestrolemia-Risk factor for Atherosclerosis Atherosclerosis

13 Hypercholesterolemia and Risk of Stroke HDL-Cardio protective Lipoprotein

14 Management of Hypercholestrolemia Life style modifications Balanced diet Exercise Stress management Drug Therapy REFERENCE Lippincott s Illustrated Review Biochemistry 5th Edition Page no. 219 to 224 THANKS

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