Lipogenesis from ketone bodies in the isolated perfused rat liver. Evidence for the cytosolic activation of acetoacetate.

The production of ketone bodies by the isolated perfused rat liver has been measured by the dilution of the specific activity of tracer amounts of beta-hydroxy[3-14C]butyrate and by accumulation in the perfusate. The latter method has been found to underestimate ketogenesis by 12 to 44% because it does not take into account acetoacetate utilization by the liver. Incorporation of ketone bodies into fatty acids and 3-beta-hydroxysterols was compared to total lipid synthesis measured by incorporation of tritium from tritiated water. A preferential labeling of 3-beta-hydroxysterols over fatty acids was observed, which is consistent with the activation of acetoacetate in the cytosol by acetoacetyl-CoA synthetase. Ketone bodies contribute 19 to 80% of the carbon incorporated into sterols and up to 22% of the carbon incorporated into fatty acids, depending upon the metabolic status of the liver. The activity of acetoacetyl-CoA synthetase is more than sufficient to account for the rate of ketone body utilization. Conditions that decrease the citrate cleavage pathway of acetyl group translocation through the mitochondrial membrane are associated with an increase in carbon flux through acetoacetyl-CoA synthetase. Formation of acetoacetate in the mitochondria and its utilization in the cytosol thus appear to be a secondary pathway of acetyl group translocation operating concurrently with the predominant citrate cleavage pathway.