3-Hydroxy-3-methylglutaryl-coenzyme A reductase activity is inhibited by cholesterol and up-regulated by sitosterol in sitosterolemic fibroblasts

Abstract Sitosterolemia is an inherited recessive disease characterized by abnormally increased plasma and tissue plant sterol concentrations. Patients hyperabsorb sitosterol. In addition, hepatic, ileal, and mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in the cholesterol biosynthetic pathway, is markedly suppressed in this disease. It is still controversial whether the down-regulation is due to accumulated sitosterol, but the effect of sitosterol on HMG-CoA reductase activity has not been studied in sitosterolemic tissues. To investigate whether sitosterol inhibits HMG-CoA reductase activity in sitosterolemia, we measured the enzyme activities in liver and cultured skin fibroblasts from patients. Hepatic HMG-CoA reductase activities in patients were decreased 76% ( P P P