Lipogenesis: Fatty Acid Synthesis - PDF

Dr Norsyahida Mohd Fauzi LIPOGENESIS Lecturer in Biopharmacy and Pharmacology Discipline, Member of Drug and Herbal Research Centre LIPOGENESIS  Lipogenesis is the formation of fat First: Simple sugar converted to fatty acid (FA synthesis)...

Dr Norsyahida Mohd Fauzi LIPOGENESIS Lecturer in Biopharmacy and Pharmacology Discipline, Member of Drug and Herbal Research Centre LIPOGENESIS  Lipogenesis is the formation of fat First: Simple sugar converted to fatty acid (FA synthesis) Second: Esterified with glycerol to form TAG (TAG synthesis) and packaged in VLDL.  Synthesis of fat occur in cytoplasm  Lipogenesis starts with acetyl-CoA  Endogenous fatty acids are synthesised in the cytosol of the liver Copyright © Pearson Education, Inc. or its affiliates. All Rights Reserved.  Fatty acid are synthesised from acetyl CoA when there is excess - Calorie intake - Dietary carbohydrate - GLUCOSE is the major source for the synthesis of FA - Dietary proteins. DE NOVO SYNTHESIS OF FATTY ACID  A large proportion of the FA used by the body is supplied by the diet (Excess carb and protein which are stored as TAG). FA synthesis occurs primarily in the liver and lactating mammary glands and, to a lesser extent, in adipose tissue. Synthesis of fatty acids Production of cytosolic acetyl CoA Carboxylation of acetyl CoA to form malonyl CoA. Major sources of the NADPH required for fatty acid synthesis Fatty acid synthase Regulation of FA synthesis Further elongation of fatty acid chains. Desaturation of fatty acid chains. PRODUCTION OF CYTOSOLIC ACETYL COA  The first step in de novo fatty acid synthesis is the transfer of acetate units from mitochondrial acetyl CoA to the cytosol.  Mitochondrial acetyl CoA is produced by oxidation of pyruvate, FA, ketone bodies and certain amino acids.  Translocation of citrate from the mitochondrion to the cytosol  Cleavage of citrate by ATP-citrate lyase to produce cytosolic acetyl CoA and OAA. CARBOXYLATION OF ACETYL COA TO FORM MALONYL COA.  MAJOR SOURCES OF THE NADPH REQUIRED FOR FATTY ACID SYNTHESIS 1. Hexose monophosphate pathway 2. The cytosolic conversion of malate to pyruvate FATTY ACID SYNTHASE malonyl CoA. A molecule of acetate is transferred from acetyl CoA to the –SH group of the acyl carrier protein (ACP). two-carbon fragment (acetate) is transferred to a temporary holding site, the thiol group of a cysteine residue on the enzyme. vacant ACP accepts a three-carbon malonate unit from malonyl CoA. The acetyl group on the cysteine residue condenses with the malonyl group on ACP (condensation). A release of carbon. The result is a four-carbon unit attached to the ACP domain. The keto group is reduced to an alcohol A molecule of water is removed (dehydrated) to introduce a double bond between carbons 2 and 3 The double bond is reduced. REGULATION OF FA SYNTHESIS 1. Phosphorylation-dephosphorylation - Insulin activates phosphatase which dephosphorylates acetyl CoA carboxylase. - Dephosphorylated form is the active form. - Glucagon & epinephrine inhibits by phosphorylating acetyl CoA carboxylase. 2. Induction/repression of enzymes - High insulin:glucagon ratio causes induction of acetyl CoA carboxylase & FA synthase. 3. Allosteric modification - Stimulated by citrate to produce FA - Inhibited by Palmitoyl CoA FURTHER ELONGATION OF FATTY ACID CHAINS.  Although palmitate, a 16-carbon, fully saturated long-chain length fatty acid (16:0), is the primary end product of fatty acid synthase activity, it can be further elongated by the addition of two-carbon units in the smooth endoplasmic reticulum (SER).  Elongation requires a system of separate enzymes rather than a multifunctional enzyme. Malonyl CoA is the two-carbon donor and NADPH supplies the electrons.  The brain has additional elongation capabilities, allowing it to produce the very- long-chain fatty acids (over 22 carbons) that are required for synthesis of brain lipids. DESATURATION OF FATTY ACID CHAINS.  Desaturases present in the SER are responsible for desaturating long-chain fatty acids (adding cis double bonds).  The desaturation reactions require NADH, cytochrome b5 and its FAD-linked reductase.  The first double bond is typically inserted between carbons 9 and 10, producing primarily 18:1(9) and small amounts of 16:1(9).  A variety of polyunsaturated fatty acids can be made through additional desaturation combined with elongation. SYNTHESIS OF TRIACYLGLYCEROL (TAG)  Synthesis of glycerol phosphate  Conversion of a free fatty acid to its activated form  Synthesis of a molecule of TAG from glycerol phosphate and fatty acyl CoA SYNTHESIS OF GLYCEROL PHOSPHATE LIVER ADIPOSE TISSUE - Glycerol phosphate can be produced from - Glycerol phosphate can be produced glucose from glucose - Glycerol kinase to convert free glycerol to glycerol phosphate CONVERSION OF A FREE FATTY ACID TO ITS ACTIVATED FORM  FA must be esterified to CoA before it can utilised for the formation of TAG  Acyl-CoA synthetase/thiokinase: A ligase enzyme; requires ATP  Form acyl-CoA compounds. SYNTHESIS OF A MOLECULE OF TAG FROM GLYCEROL PHOSPHATE AND FATTY ACYL COA LIVER  TAG synthesis begins with glycerol-3-phosphate.  Glycerol is first phosphorylated by glycerol kinase and then activated fatty acids (fatty acyl-CoAs) serve as substrates for fatty acid addition generating phosphatidic acid.  The phosphate group is then removed and the last fatty acid is added. SMALL INTESTINE  In the small intestine, dietary TAGs are hydrolyzed to free fatty acids and monoacylglycerides (MAGs) prior to uptake by the enterocytes.  The enterocyte MAGs serve as substrates for acylation in a two-step process yielding a TAG. ADIPOSE TISSUE  Within adipose tissue there is no expression of glycerol kinase so the building block for TAG in this tissue is the glycolytic intermediate, dihydroxyacetone phosphate, DHAP.  The DHAP is reduced to glycerol-3-phosphate by cytosolic glycerol-3-phosphate dehydrogenase and the remaining reaction of TAG synthesis are the same as for all other tissues. SYNTHESIS OF VLDL 1. Protein synthesized in RER 2. Packaged with TG in ER and Golgi complex to form VLDL 3. VLDL are transported to the cell membrane in secretory vesicle and secreted by exocytosis FATE OF VLDL LIPID METABOLISM DURING FED STATE SYNTHESIS OF MAJOR MEMBRANE LIPIDS