Lipid Metabolism PDF

## Lipid Metabolism **Lipids** - are esters of fatty acids with glycerol called triglycerides. ### Metabolic Pathways of Lipids **Exogenous Lipids:** - Dietary lipids are ingested in form of triglycerides (98%), phospholipids, cholesterol. - Digestion of triacylglycerols - in small intestin...

## Lipid Metabolism **Lipids** - are esters of fatty acids with glycerol called triglycerides. ### Metabolic Pathways of Lipids **Exogenous Lipids:** - Dietary lipids are ingested in form of triglycerides (98%), phospholipids, cholesterol. - Digestion of triacylglycerols - in small intestine - Pancreatic lipases in small intestine. **Endogenous Lipids: ** - Lipogenesis - Lipolysis ### Functions of Triglyceride - Main stored form of energy in adipose cells. - Lipids are a good source of energy as 1 gm supplies 9 Kcalories (9kcal/gram). ### Lipogenesis **Definition:** The synthesis of (Triacylglycerol) TAG from fatty acids and glycerol. **Site:** - Sub-cellular site: cytoplasm (cytosol) - Organ (tissue) site: liver (primary site), adipose tissue, lactating mammary gland, kidney. **Processes:** 1. Biosynthesis of glycerol 2. Biosynthesis of fatty acids. 3. Biosynthesis of the triacylglycerol. **1. Activation of glycerol. (Synthesis of glycerol-3-P)** - Glycerol-3P is the precursor for membrane lipids and TAG **How to form glycerol-3-P?** 1. **From Glucose:** - via glycolysis --> dihydroxyacetone phosphate (DHAP) --> reduced to glycerol-3 phosphate by the enzyme glycerol-3 phosphate dehydrogenase. 2. **From Glycerol:** - by the enzyme glycero kinase. **Key notes:** - **In Liver:** glycerol kinase is present, so glycerol-3Phosphate is formed from both glucose and glycerol. - **In adipose tissue:** glycerol kinase is absent, so glycerol-3Phosphate is formed only from glucose. ### 2-Biosynthesis of fatty acids **Site:** Cytoplasmic (cytosol) FA synthesis. **Many tissues, especially liver, kidney, brain, lung, lactating mammary gland and adipose tissue.** **Substrate:** (building block of fatty acid synthesis): acetyl-CoA (active acetate) 1. Glucose is oxidized via glycolysis to pyruvate which undergoes oxidative decarboxylation, forming acetyl-CoA within mitochondria. **How to move acetyl-CoA to cytoplasm?** **by Citrate shuttle.** 2. Condensation of Acetyl CoA with oxalacetate to form citrate which can pass out mitochondrial membrane. 3. Translocation of Citrate from mitochondria to cytoplasm. **In cytoplasm:** 1. Citrate splits again by ATP citrate lyase enzyme into acetyl-CoA and OAA. **Key note:** Cytoplasmic (Extramitochondrial) FA synthesis is the only system responsible for de novo synthesis of FA from active acetate. 2. Oxaloacetate converted to malate by malate dehydrogenase. 3. Malate is converted to pyruvate by malic enzyme, producing 1 NADPH. ### Main requirements de novo synthesis of FA: 1. **Acetyl CoA (Active Acetate)**: Acetyl-CoA used for FA synthesis is derived from glucose and NEVER from FA. 2. **ATP** (provides energy). 3. **NADPH** (reduced coenzyme): reducing power. - What is NADPH? NADH with a phosphate group. **NADPH** is produced in the cytosol by both: - Malic enzyme - Pentose phosphate pathway (primary source). 4. **Acetyl CoA carboxylase** (Key regulatory enzyme) 5. **Fatty acid synthase** - acyl carrier protein (ACP) ### Biosynthesis of Fatty acids **First Reaction of fatty acid synthesis** - Acetyl CoA is converted to malonyl CoA. **Key regulatory step** - Acetyl CoA carboxylase that: - consumes ATP and requires the irreversible regulatory step in fatty acid synthesis. - biotin as a cofactor. - The enzyme catalyzes the rate-limiting reaction. ### REGULATION: **Acetyl CoA Acetyl CoA Carboxylase Malonyl CoA** - **Hormonal Allosteric:** - **I- short-term regulation of acetyl CoA carboxylase:** - Citrate - Malonyl CoA - Palmitoyl CoA - Insulin - Glucagon - Epinephrine - **II- long-term regulation of acetyl CoA carboxylase:** - High-calorie, high-carbohydrate diets - Low-calorie diet or fasting **Role of malonyl-CoA:** serves as activated donor of acetyl group (2C) in FA synthesis. ### Second reaction of fatty acid synthesis - Palmitic acid is the end product of fatty acid pathway. - The reactions in the synthetic process are catalyzed by a multi-enzyme complex, fatty acid synthase. - It is a dimer. - Each unit contains 7 enzymes and a protein (acyl carrier protein). - The carbon chain lengthens by two carbons each cycle. - Each cycle is a repeating four-step sequence: **Step** **Reaction** **Enzyme** --------- ------------------------------------------ ------------------------------------------ 1 Condensation β-Ketoacyl synthase 2 Reduction β-Ketoacyl-ACP reductase 3 Dehydration β-Hydroxyacyl-ACP dehydretase 4 Reduction Enoyl-ACP reductase - When reaches 16 carbons, the product leaves the cycle. - Then the seven cycles produce the 16-carbon saturated palmitoyl group (Palmitic Acid). ### Overall reaction: Acetyl-CoA + 7malonyl-CoA + 14NADPH + 14H+ --> palmitate + 7CO2 + 8CoA + 14NADP+ + 6H2O ### Activation of fatty acids (synthesis of acyl-CoA) - by acyl CoA synthetase - to be able to bind with G3P in next steps. ### 3-Synthesis of the triacylglycerol. - is formed by estrification of 3 molecules fatty acids with one molecule of glycerol-3 phosphate. - Enzyme: GP Acyl transferase ### 1- Fates of the formed TAG: - **In liver:** TAG --> VLDL --> to adipose tissues - **In adipose tissue:** TAG stored as depot fat ### Regulation of lipogenesis - Insulin stimulates lipogenesis - Adipocytes can take glucose only in the presence of insulin - Insulin stimulates glycolysis which supplies glycerol phosphate - Anti-insulin hormones inhibit lipogenesis. ### After meal: Insulin **Stimulates both:** - glucose oxidation --> Acetyl CoA - lipogensis (= FA synthesis) **Inhibits:** - lipolysis --> FA - FA oxidation --> Acetyl CoA