最新国外大学-脂肪代谢生理基础.ppt

Fatty Acid Metabolism Introduction of Clinical Case 10 m.o. girl Overnight fast, morning seizures coma [glu] = 20mg/dl iv glucose, improves rapidly Family hx Sister hospitalized with hypoglycemia at 8 and 15 mo., died at 18 mo after 15 hr fast Introduction of Clinical Case Lab values RBC count, urea, bicarbonate, lactate, pyruvate, alanine, ammonia all WNL Urinalysis normal (no organic acids) Monitored fast in hospital @ 16 hr, [glu]=19mg/dl No response to intramuscular glucagon [KB] unchanged during fast Liver biopsy, normal mitochondria, large accumulation of extramitochondrial fat [carnitine normal] Carnitine acyltransferase activity undetectable Given oral MCT [glu] = 140mg/dl (from 23mg/dl) [Acetoacetate] = 86mg/dl (from 3mg/dl), similar for B-OH-butyrate Discharged with recommendation of 8 meals per day Overview of Fatty Acid Metabolism: Insulin Effectsfigure 20-1 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 glycolysis Overview of Fatty Acid Metabolism: Glucagon/Epinephrine Effectsfigure 20-2 Adipose increased TG mobilization hormone-sensitive lipase Increased FA oxidation all tissues except CNS and RBC Fatty Acid Synthesisfigure 20-3 Glycolysis cytoplasmic PDH mitochondrial FA synthesis cytoplasmic Citrate Shuttle moves AcCoA to cytoplasm produces 50% NADPH via malic enzyme Pyruvate malate cycle Fatty Acid Synthesis PathwayAcetyl CoA Carboxylase ‘first reaction’ of fatty acid synthesis AcCoA + ATP + CO2 malonyl-CoA + ADP + Pi malonyl-CoA serves as activated donor of acetyl groups in FA synthesis Fatty Acid Synthesis PathwayFA Synthase Complexfigure 20-4 Priming reactions transacetylases (1) condensation rxn (2) reduction rxn (3) dehydration rxn (4) reduction rxn Regulation of FA synthesis: Acetyl CoA Carboxylase Allosteric regulation stimulated by citrate feed forward activation inhibited by palmi