The regulation of acetoacetyl-CoA synthetase activity by modulators of cholesterol synthesis in vivo and the utilization of acetoacetate for cholesterogenesis.

[3-14C]Acetoacetate, injected subcutaneously into rats, was rapidly incorporated into hepatic cholesterol and fatty acids. Injection of radiolabeled acetoacetate, acetate, or glucose resulted in the preferential incorporation of acetoacetate into cholesterol. The postmitochondrial supernatant of a rat liver homogenate has the capacity to synthesize radiolabeled sterols from [3-14C]acetoacetate, and this capacity surpasses its capacity to utilize [1-14C]acetate. The activity of acetoacetyl-CoA synthetase, a cytoplasmic enzyme that activates acetoacetate, was found to be highly regulated by modulators known to affect the activity of 3-hydroxy-3-methylglutaryl-CoA reductase and/or cholesterol biosynthesis in liver and adrenals of adult rats. Acetoacetyl-CoA synthetase activity was depressed by feeding cholesterol or mevalonate administration and was enhanced by the addition to the diet of mevinolin and/or cholestyramine. The activity of acetoacetyl-CoA synthetase in adrenals was enhanced by treatment of the animals with 4-aminopyrazolopyrimidine. These changes in activity of acetoacetyl-CoA synthetase were in synchrony with changes in the activities of 3-hydroxy-3-methylglutaryl-CoA synthase and 3-hydroxy-3-methylglutaryl-CoA reductase. The evidence suggests that the regulation of acetoacetyl-CoA synthetase activity and the utilization of acetoacetate for lipogenesis is closely linked to the regulation of cholesterogenesis.