Medical Biochemistry, First Year MBBS & Dentistry Program - UMM AL-QURA UNIVERSITY PDF

Medical Biochemistry First Year – MBBS & Dentistry program  (Lipid Metabolism I) Lipid Transport ILOs - Illustrate the structure of the lipoprotein particle. - Identify the four major groups of plasma lipoproteins, structure, and its function. - Mention types, causes, and manifestation of s...

Medical Biochemistry First Year – MBBS & Dentistry program  (Lipid Metabolism I) Lipid Transport ILOs - Illustrate the structure of the lipoprotein particle. - Identify the four major groups of plasma lipoproteins, structure, and its function. - Mention types, causes, and manifestation of some lipoprotein disorders and fatty liver.  Plasma Lipoproteins (Structure) All the lipids contained in plasma, including fat, phosphalipids, cholesterol, cholesterol ester and fatty acid, exist and transport in the form of lipoprotein Non-covalent assemblies of lipids and proteins LP core ✓ Triglycerides ✓ Cholesterol esters LP surface ✓ Phospholipids ✓ Proteins ✓ cholesterol Function as transport vehicles for triacylglycerols and cholesterol in the blood Lipoprotein Composition CM (chylomicron ) very low density lipoprotein ( VLDL) low density lipoprotein ( LDL) high density lipoprotein (HDL) CM VLDL LDL HDL Major Apo B 48 Apo B 100 Apo B 100 Apo A-I Protein Major TG TG CE CE Lipid  Lipids are Transported as Lipoproteins  All lipids in plasma are transported in the form of lipoproteins.  Transport of dietary lipids (exogenous lipids) from intestine to all tissues by lipoprotein called Chylomicrons  Transport of lipids (endogenous lipids) from liver to peripheral tissues by lipoprotein called VLDL (very low density lipoproteins).  Apolipoproteins (apoproteins) Functions of Apo-lipoproteins 1. To combine and transport lipids. 2. To recognize the lipoprotein receptors Apo-B 100 is the ligand for LDL-receptors Apo-B 48 for chylomicron Apo-A1 is the ligand for HDL receptor. 3. Activators for certain enzymes involved in lipoprotein metabolism Apo C II activates lipoprotein lipase and Apo-A1 activates LCAT (Lecithin Cholesterol Acyltransferase, formation of cholesterol esters in lipoproteins). Chylomicrons Synthesized in small intestine, Transport dietary lipids (exogenous TG) 98% lipid, large sized, lowest density Apo B-48 (Receptor binding) Apo C-II (Lipoprotein lipase activator) Apo E. (Remnant receptor binding) Very Low Density Lipoprotein (VLDL) ✓ Synthesized in liver, Transport endogenous triglycerides ✓ 90% lipid, 10% protein ✓ Apo B-100 (Receptor binding) ✓ Apo C-II (LPL activator). ✓ Apo E. (Remnant receptor binding) ✓ The major fraction of VLDL remnant further loses TG, so as to be converted to LDL Low Density Lipoprotein LDL Formation : from VLDL in blood, but a small part is directly released from liver Function: transport cholesterol from liver to the peripheral tissues. Carries aprox. 50% of blood cholesterol. contains only apo B-100. Expulsion cholesterol from the cell, and transported by HDL and finally excreted through liver. LDL concentration in blood has positive correlation with incidence of cardiovascular diseases.  Formation site: liver and intestine Function: 1. transport cholesterol from peripheral tissues to liver (reverse cholesterol transport), (Removing free cholesterol from extra hepatic tissues and esterifing it using LCAT ). 2. Act as a source for apo C and apo E that are required in the metabolism of chylomicrons & VLDL 3. Transport phospholipids from liver to tissues.  Liver converted cholesterol to bile acids.  Protects against heart disease Types of Lipoprotein Disorders Hyperlipoproteinemia  Also known as hyperlipidemia. A group of disorders characterized by increased plasma lipoproteins. It can be classified into 5 types Each of which may be familial or acquired. Hyperlipidemia Type I: familial type caused by deficiency of lipoprotein lipase enzyme. Characterized by increased plasma chylomicrons and the plasma is turbid. Hyperlipidemia Type II: familial type caused by reduced LDL metabolism due to defective LDL receptors. There is marked increase in plasma cholesterol (familial hypercholesterolemia).  Type III (Dysbeta lipoproteinemia): familial type caused by defective apo E necessary for uptake and metabolism of VLDL and chylomicron remnants by liver. Characterized by both hypercholesterolemia & hypertriacylglycerodemia. Type VI (Hyperprebetalipoproteinemia): familial type is due to increased formation of triacylglycerols from carbohydrates. Characterized by increased plasma VLDL , triaclglycerols & some increase in plasma cholesterol The plasma is turbid. Type V (Hyperchylomicronemia & Hyperprebetalipoproteinemia). Usually associated with obesity and glucose intolerance. Characterized by increased chylomicrons and VLDL and increase triacylglycerols. The plasma is turbid. The cause of disease is unknown, but may be due to increase formation of apo- B. ▪ Description: Metabolic disorder in LP production. allowing TG to accumulate in liver. ▪ May be occurred during starvation and high-fat diet - and in un- controlled diabetes.  (Lipid Metabolism II) Lipid Biosynthesis ILOs - Describe the mechanism of fat biosynthesis and its regulation - Illustrate the enzymes required in fatty acid biosynthesis. - Describe the synthesis of unsaturated fatty acids. Fatty Acid Synthesis (Lipogenesis) Lipogenesis in mammals occurs primarily in liver and adipose tissues (also in brain, kidney, mammary glands during lactation). It occurs in cytosol with immediate substrate Acetyl-CoA. Lipogenesis and lipolysis occur by different routes. It requires co-factors, NADPH, ATP, Mn2+, biotin, and HCO3. There are four major differences between fatty acid breakdown and biosynthesis Lipogenesis (Triacylglycerol synthesis) Definition: Lipogenesis is the synthesis of TAG from fatty acids and glycerol. Site: Sub-cellular site; cytoplasm Organ (tissue) site: liver (primary site), adipose tissue, lactating mammary gland, kidney Esters of glycerol with three fatty acids Functions of Triglyceride: Main stored form of energy in adipose cells. Energy: 9 kcal/g I) Biosynthesis of glycerol-3P Glucose is oxidized via glycolysis to dihydroxy acetone phosphate ➔ reduced to glycerol-3 phosphate by the enzyme glycerol-3 phosphate dehydrogenase. Liver, Adipose + Liver only Muscles Biosynthesis of glycerol-3P In Liver, glycerokinase is present, so In adipose tissue gycerokinase is absent, glycerol phosphate is formed from both so glycerol phosphate is formed only from glucose & glycerol. glucose. II) Biosynthesis of fatty acids Site: Many tissues, especially liver, kidney, brain, lung, lactating mammary gland and adipose tissue. Main requirements for de novo synthesis of FA: 1. Acetyl CoA (Active Acetate) 2. Acetyl CoA carboxylase (Key regulatory enzyme) 3. Fatty acid synthase 4. ATP & NADPH Palmitic acid is the end product of fatty acid pathway. Steps of Biosynthesis of fatty acids Step 1: Formation of Acetyl-CoA from Pyruvate Acetyl-CoA, the main building block for FA synthesis is formed from carbohydrate via oxidation of pyruvate within mitochondria. Acetyl-CoA, formed from pyruvate within mitochondria, does not diffuse readily to cytoplasm (principle site for FA synthesis).  Translocation of acetyl CoA from mitochondria to the cytoplasm involves condensation with oxalacetate to form citrate which can pass out mitochondrial membrane.  Citrate is splitted again by ATP citrate lyase enzyme into acetyl-CoA and OAA. Acetyl-CoA used for FA synthesis is derived from glucose and NEVER from FA. After meal: Insulin stimulates both glucose oxidation (➔ Acetyl CoA), lipogensis (= FA synthesis) and inhibits lipolysis (➔ FA oxidation ➔ Acetyl CoA)  Acetyl CoA is converted to malonyl CoA, an important intermediate in fatty acid synthesis, by acetyl CoA carboxylase that consumes ATP and requires biotin as a cofactor. Key regulatory enzyme Step 6: Condensation of Acetyl CoA and malonyl CoA by Fatty acid synthase Fatty acid synthase multienzyme complex. It is a dimer. Each unit contains 7 enzymes and a protein (acyl carrier protein) Palmitate, a 16-carbon saturated fatty acid, is the final product of fatty acid synthesis pathway. 1- Condensing enzyme (β-Ketoacyl synthase) (KS) 2- β-Ketoacyl-ACP reductase (KR) 3- β-Hydroxyacyl-ACP dehydratase (DH) 4- Enoyl-ACP reductase (ER)  Repetition of 4 steps leads to fatty acid synthesis When reaches 16 carbons, the product leaves the cycle. All the reactions in the synthetic process are catalyzed by a multi-enzyme complex, fatty acid synthase.  The Overall Reaction Of FA Synthesis Then the seven cycles of condensation and reduction produce the 16-carbon saturated palmitoyl group (palmitic acid) The Overall Reaction is: Acetyl-CoA + 7Malonyl-CoA + 14NADPH + 14H+ ➔ Palmitate + 7CO2 + 8CoASH + 14NADP+ + 6H2O The biosynthesis of FAs requires acetyl-CoA and the input of energy in the form of ATP and reducing power of NADPH. Step 7: Fatty acid convert into acyl CoA by acyl CoA synthetase Fatty acid convert into acyl CoA by acyl CoA synthetase to be activate FA and to be able to bind with G3P in next steps. III) Synthesis of TG Step 8: Esterification of FA with G3P Finally, triacylglycerol is formed by esterification of fatty acids with glycerol-3 phosphate using GP acyl transferase  ➔ Step 9: Oxaloacetate is converted to malate by malate dehydrogenase. Step 10: Malate is converted to pyruvate by malic enzyme, producing 1 NADPH. a) NADPH is required for synthesis of palmitate and elongation of fatty acids. b) NADPH is produced in the cytosol by both malic enzyme and the pentose phosphate pathway, which is the primary source. II) Biosynthesis of fatty acids (Overview) 38 Biosynthesis of fatty acids 9 10 10 39 Regulation of Fatty Acid Synthesis  Regulation of Lipogenesis Active form Insulin Inactive Insulin stimulates lipogenesis Adipocytes can take glucose only in the presence of insulin Insulin stimulate glycolysis which supplies glycerol phosphate Anti-insulin hormones inhibit lipogenesis 23 Fates of the formed TAG In liver: TAG ➔ VLDL ➔ tissues In adipose tissue: TAG stored as depot fat