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The Journal of Lipid Research, Vol. 39, 44-50, January 1998
Copyright © 1998 by Lipid Research, Inc.
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 7-reductase in liver and mononuclear leukocytes
Akira Hondaa,
Gerald Salena,
Lien B. Nguyena,
G. Stephen Tinta,
Ashok K. Battaa, and
Sarah Shefera
a Departments of Medicine and Liver Center, the University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, and Veterans Affairs Medical Center, East Orange, NJ 07018
Correspondence to:
Akira Honda.
Sitosterolemia is a recessively inherited disorder characterized by abnormally increased plasma and tissue plant sterol concentrations. Patients have markedly reduced whole body cholesterol biosynthesis associated with suppressed hepatic, ileal, and mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in cholesterol biosynthetic pathway, coupled with significantly increased low density lipoprotein (LDL) receptor expression. To investigate the mechanism of down-regulated cholesterol biosynthesis, we assayed several other key enzymes in the cholesterol biosynthetic pathway including acetoacetyl-CoA thiolase, HMG-CoA synthase, squalene synthase, and 7-dehydrocholesterol 7-reductase activities in liver and freshly isolated mononuclear leukocytes from four sitosterolemic patients and 19 controls. Hepatic acetoacetyl-CoA thiolase, HMG-CoA synthase, reductase, and squalene synthase activities were significantly decreased (P < 0.05) -39%, -54%, -76%, and -57%, respectively, and 7-dehydrocholesterol 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 also found in mononuclear leukocytes from a sitosterolemic patient. Thus, reduced cholesterol synthesis is caused not only by decreased HMG -CoA reductase but also by the coordinate down-regulation of entire pathway of cholesterol biosynthesis.
These results suggest that inadequate cholesterol production in sitosterolemia is due to abnormal down-regulation of early, intermediate, and late enzymes in the cholesterol biosynthetic pathway rather than a single inherited defect in the HMG -CoA reductase gene. Honda, A., G. Salen, L. B. Nguyen, G. S. Tint, A. K. Batta, and S. Shefer. 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 7-reductase in liver and mononuclear leukocytes. J. Lipid Res. 1998. 39: 4450.
Supplementary key words:
LDL receptor, sitosterol

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Copyright © 1998 by the American Society for Biochemistry and Molecular Biology.
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