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Download Triacylglycerol Metabolism Gone Bad: A major cause of disease
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Fatty Acid Synthesis • Fatty Acid Synthase – Acetyl-CoA serves as a primer – Addition of two-carbon units from malonyl-CoA – Each two-carbon unit added must be reduced by 2 NADPH + 2 H+ – Reaction for the synthesis of Palmitic acid (C:16): Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH + 14H+ Palmitic acid + 7 CO2 + 14 NADP+ + 8 CoA + 6 H2O Cytosolic Acetyl-CoA & NADPH Generation (presented as in most text books, this scheme ignores the specificities of mitochondrial transporters; a more accurate description is in the handout) Glycolysis Mitochondrion Acetyl-CoA Pyruvate Pyruvate Oxaloacetate TCA cycle Citrate Malate Citrate Cytosol Citrate lyase Malic enzyme Pyruvate Malate dehydrogenase Malate NADPH NADP+ + H+ + CO2 ATP + CoA ADP + Pi Oxaloacetate + Acetyl-CoA NAD+ NADH+H+ Fatty acid synthesis Acetyl-CoA carboxylase ATP + CO2 ADP + Pi Malonyl-CoA Fatty Acid Synthesis • Malonyl-CoA is produced by Acetyl-CoA carboxylase O || CH3-C-S-CoA O O || || - O-C-CH -C-S-CoA 2 Acetyl-CoA (cytoplasmic) + HCO3- ATP Malonyl-CoA ADP + Pi Acetyl-CoA Carboxylase Requires Biotin Fatty Acid Synthesis • Acetyl-CoA Carboxylase – Rate limiting reaction for fatty acid synthesis – ACC1 is a liver isozyme – Small amounts of ACC2 are present in muscle where malonyl-CoA has a regulatory function (Fatty acid oxidation) Fatty Acid Synthesis • Acetyl-CoA Carboxylase 1 – Highly regulated • Allosteric activation by citrate; inhibition by palmitoyl-CoA. • Inhibited by phosphorylation in the fasting state. – (low blood glucose inhibits; phosphorylation state is determined by both glucagon activation of a kinase and insulin activation of a phosphatase). • Transcriptional up regulation by ChREBP (high carbohydrate diet increases amount of ACC1 and most other enzymes of fatty acid synthetic pathway) Fatty Acid Synthesis Transcriptiona l control Acetyl-CoA Carboxylase 1 Xylulose-5phosphate + Insulin H2O PP Phosphorylated Acetyl CoA carboxylase (Inactive) Acetyl-CoA Transcription Citrate Palmitoyl-CoA Pi + + Protein phosphatase PKA AMPK ADP + Pi + Glucagon Covalent modification + ATP AMP ─ CO2 ATP Acetyl CoA carboxylase (Inactive) Acetyl CoA carboxylase (Active) ADP + Pi Malonyl-CoA Allosteric regulation Triacylglycerol Synthesis • Long-term transcriptional regulation by ChREBP (Carbohydrate Regulatory Element Binding Protein). – In addition to short term regulation of Acetyl-CoA carboxylase – Many enzymes of fatty acid & triacylglycerol synthetic pathway are coordinately regulated by ChREBP. – ChREBP is inhibited by Protein Kinase A dependent phosphorylation. – ChREBP is activated by Protein Phosphatase 2A dependent dephophorylation (PP2A is stimulated by Xyulose-5-P). Low Glucose: Glucagon cAMP Protein kinase A Inactive ChREPB-P Fatty acid synthesis High Glucose: Xyulose-5-P Protein Phosphatase A2 Active ChREPB-OH Fatty acid synthesis Fatty Acid Synthesis • The main product of fatty acid synthase is palmitic acid (16:0). • Fatty acids can be elongated by other enzymes that add two carbon units from malonyl-CoA. Elongation is particularly important in brain. • Still other enzymes can add double bonds (usually at 9 ). Omega-3 and omega-6 fatty acids can not be synthesized by humans. Triacylglycerol Synthesis • Fatty acids must be activated to Acyl-CoA Fatty acid + CoA + ATP Acyl-CoA + AMP + PPi Acyl-CoA synthetase PPi + H2O 2 Pi Pyrophosphatase Triacylglycerol Synthesis • Glycerol-3-phosphate is required for triacylglycerol synthesis. H2C-OH | HOCH O | | H2C-O-P-O || O- H2C-OH | O=C O | | H2C-O-P-O || O- Glycerol-3-phosphate dehydrogenase Dihydroxyacetone Phosphate Glycerol-3-phosphate NADH + H+ NAD+ Glycerol-3-phosphate dehydrogenase Triacylglycerol Synthesis • Addition of 3 Acyl groups from Acyl-CoA to Glycerol-3-phosphate O || O H2C - O - C - R1 || | R2 - C - O - CH | H2C - O - C - R3 || O H2C-OH | HO-CH O | | H2 C-O-P-O || O- Glycerol-3-phosphate 2 Acyl-CoA Phosphatidate CoA Acyl-CoA Triacylglycerol CoA + Pi VLDL formation Apolipoprotien B-100 has a repeating -helix/-sheet structure: Lipids are packaged as apolipoprotein B-100 is being synthesized: From Shelness & Sellers (2001) Curr Opin Lipidology 12:151-157 VLDL formation • VLDL stands for Very Low Density Lipoprotein • As it is synthesized, VLDL contains: • • • • One molecule of apoliprotein B-100 Triacylglycerol Phospholipid Cholesterol ester • Microsomal Triacylglycerol Transfer Protein(MTP) assists in the formation of the VLDL • Other components are added to the VLDL in the blood. VLDL formation • Apolipoprotein B-100 synthesis is required for the transport of lipid out of the liver – If protein synthesis is reduced (e.g. by malnutrition) fat droplets accumulate in the liver. – If the rate of lipid synthesis is greatly elevated with respect to protein synthesis (e.g. in type I diabetes or glucose 6-phosphatase deficiency) fat droplets accumulate in the liver.