Effect of insulin on ketogenesis and fatty acid synthesis in rat hepatocytes incubated with dichloroacetate.
In parenchymal liver cells isolated from fed rats, insulin increased the formation of 14CO2 from [1-14C]pyruvate (and presumably the flux through pyruvate dehydrogenase) by 14%. Dichloroacetate, an activator of the pyruvate dehydrogenase complex, stimulated this process by 133%. As judged from the conversion of [2-14C]pyruvate to 14CO2, the tricarboxylic acid cycle activity was not affected by insulin, but it was depressed by dichloroacetate. In hepatocytes from fed rats, incubated with glucose as the only carbon source, dichloroacetate caused a stimulation (31%) of fatty acid synthesis, measured as 3H incorporation from 3H2O into fatty acid, and an increased (134%) accumulation of ketone bodies (acetoacetate + D-3-hydroxybutyrate). Dichloroacetate did not affect ketone body formation from [14C]palmitate, suggesting that the increased accumulation of ketone bodies resulted from acetyl-CoA derived from pyruvate. Insulin stimulated fatty acid synthesis in hepatocytes from fed rats. In the combined presence of insulin plus dichloroacetate, fatty acid synthesis was more rapid than in the presence of either insulin or dichloroacetate, whereas the accumulation of ketone bodies was smaller than in the presence of dichloroacetate alone. Although pyruvate dehydrogenase activity, which is rate-limiting for fatty acid synthesis in hepatocytes from fed rats, is stimulated both by insulin and by dichloroacetate, the reciprocal changes in fatty acid synthesis and ketone body accumulation brought about by insulin in the presence of dichloroacetate suggest that insulin is also involved in the regulation of fatty acid synthesis at a mitochondrial site after pyruvate dehydrogenase, possibly at the partitioning of acetyl-CoA between citrate and ketone body formation.
D000085:Acetates / Q000494:pharmacology*; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002245:Carbon Dioxide / Q000378:metabolism; D002951:Citrates / Q000378:metabolism; D019343:Citric Acid; D003999:Dichloroacetic Acid / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005227:Fatty Acids / Q000096:biosynthesis*; D005260:Female; D007328:Insulin / Q000494:pharmacology*; D007657:Ketone Bodies / Q000096:biosynthesis*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D011768:Pyruvate Dehydrogenase Complex / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D019289:Pyruvic Acid; D051381:Rats; D011919:Rats, Inbred Strains
D000085:Acetates; D002951:Citrates; D005227:Fatty Acids; D007328:Insulin; D007657:Ketone Bodies; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; D002245:Carbon Dioxide; D019343:Citric Acid; D000105:Acetyl Coenzyme A; D019289:Pyruvic Acid; D003999:Dichloroacetic Acid