DOWN-REGULATION OF CHOLESTEROL-BIOSYNTHESIS IN SITOSTEROLEMIA - DIMINISHED ACTIVITIES OF ACETOACETYL-COA THIOLASE, 3-HYDROXY-3-METHYLGLUTARYL-COA SYNTHASE, REDUCTASE, SQUALENE SYNTHASE, AND 7-DEHYDROCHOLESTEROL DELTA(7)-REDUCTASE IN LIVER AND MONONUCLEAR LEUKOCYTES

Sitosterolemia is a recessively inherited disorder characterized by ab normally increased plasma and tissue plant sterol concentrations. Pati ents have markedly, reduced whole body cholesterol biosynthesis associ ated with suppressed hepatic, ileal, and mononuclear leukocyte 3-hydro xy- 3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controll ing enzyme in cholesterol biosynthetic pathway, coupled with significa ntly increased low density lipoprotein (LDL) receptor expression. To i nvestigate the mechanism of downregulated cholesterol biosynthesis, we assayed several other key enzymes in the cholesterol biosynthetic pat hway including acetoacetyl-CoA thiolase, HMG-CoA synthase, squalene sy nthase, and 7-dehydrocholesterol Delta(7)-reductase activities in live r and freshly isolated mononuclear leukocytes from four sitostreolemic patients and 19 controls. Hepatic acetoacetyl- CoA thiolase. HMG-CoA synthase, reductase, and squalene synthase activities were significant ly decreased (P < 0.05) -39%, -54%, -76%, and -57%, respectively, and 7-dehydrocholesterol Delta(7)-reductase activity tended to be lower (- 35%) in the sitosterolemic compared with control subjects. The reduced HMG-CoA synthase, reductase, and squalene synthase activities were al so found in mononuclear leukocytes from a sitosterolemic patient. Thus , reduced cholesterol synthesis is caused not only by decreased HMG-Co A reductase but also by the coordinate down-regulation of entire pathw ay of cholesterol biosynthesis. These results suggest that inadequate cholesterol production in sitosterolemia is due to abnormal down-regul ation of early, intermediate, and late enzymes in the cholesterol bios ynthetic pathway rather than a single inherited defect in the HMG-CoA reductase gene.