The Regulation of Ketogenesis from Octanoic Acid

The regulation of ketogenesis in the rat has been studied both in uiuo and in the isolated perfused liver with octanoic acid as substrate. This fatty acid, which is not utilized directly for triglyceride synthesis, was chosen in order to investigate the events that govern the metabolism of fatty acids subsequent to the (?-oxidation process. Experiments in viuo established that for any given load of octanoate, fasted animals produced ketones at a much faster rate than normal animals and that insulin had no inhibitory effect on this response. Qualitatively similar results were obtained with the isolated perfused liver. Livers from alloxan diabetic rats produced ketones at maximal rates independent of the fatty acid concentration in the perfusion fluid. With high concentrations of octanoate, livers from fasted animals, unlike those from normal animals, could be induced to synthesize ketones at a rate approximately equal to that of the diabetic group. Perfusion studies with octanoate-l-14C revealed that the activity of the tricarboxylic acid cycle, although modestly depressed in the ketotic state, exerted only a minor modulating influence on the rate of ketogenesis. Surprisingly, the depression of lipogenesis accompanying fasting was found to be of sufficient magnitude to account for a major proportion of the increased Cz unit flux into ketone bodies. The block in lipogenesis alone could not account for the markedly elevated rate of ketogenesis seen in the diabetic state in which an accelerated generation of acetyl-CoA appeared to be the dominant feature.