Fatty Acid Metabolism
1. Fatty acid synthesisInsulin Effects figure 1
Liver increased fatty acid synthesis glycolysis, PDH, FA synthesis increased TG synthesis and transport as VLDL Adipose increased VLDL metabolism lipoprotein lipase increased storage of lipid glycolysisOverview of Fatty Acid Metabolism: Glucagon/Epinephrine Effects figure 2
Adipose increased TG mobilization hormone-sensitive lipase Increased FA oxidation all tissues except CNS and RBCFatty Acid Synthesis figure 3
Glycolysis cytoplasmic PDH mitochondrial FA synthesis cytoplasmic Citrate Shuttle moves AcCoA to cytoplasm produces 50% NADPH via malic enzyme Pyruvate malate cycleFatty Acid Synthesis Pathway Acetyl CoA Carboxylase
‘first reaction’ of fatty acid synthesisAcCoA + ATP + CO2 malonyl-CoA + ADP + Pimalonyl-CoA serves as activated donor of acetyl groups in FA synthesisFatty Acid Synthesis Pathway FA Synthase Complex figure 4
Priming reactions transacetylases (1) condensation (2) reduction (3) dehydration (4) reduction
Regulation of FA synthesis: Acetyl CoA Carboxylase
Allosteric regulation stimulated by citrate feed forward activation inhibited by palmitoyl CoA hi B-oxidation (fasted state) or esterification to TG limiting Inducible enzyme Induced by insulin Repressed by glucagonRegulation of FA synthesis: Acetyl CoA Carboxylase figure 5
Covalent Regulation Activation (fed state) insulin induces protein phosphatase activates ACC Inactivation (starved state) glucagon increases cAMP activates protein kinase A inactivates ACCLipid Metabolism in Fat Cells: Fed State figure 6
Insulin stimulates LPL increased uptake of FA from chylomicrons and VLDL stimulates glycolysis increased glycerol phosphate synthesis increases esterification induces HSL-phosphatase inactivates HSL net effect: TG storageLipid Metabolism in Fat Cells: Starved or Exercising State figure 7
Glucagon, epinephrine activates adenylate cyclase increases cAMP activates protein kinase A activates HSL net effect: TG mobilization and increased FFAOxidation of Fatty Acids The Carnitine Shuttle figure 8
B-oxidation in mitochondria IMM impermeable to FA-CoA transport of FA across IMM requires the carnitine shuttleB-Oxidation figure 9
FAD-dependent dehydrogenation hydration NAD-dependent dehydrogenation cleavageCoordinate Regulation of Fatty Acid Oxidation and Fatty Acid Synthesis by Allosteric Effectors figure 10
Feeding CAT-1 allosterically inhibited by malonyl-CoA ACC allosterically activated by citrate net effect: FA synthesis Starvation ACC inhibited by FA-CoA no malonyl-CoA to inhibit CAT-1 net effect: FA oxidation