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
A. Honda et al., 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, Journal of lipid research, 39(1), 1998, pp. 44-50
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.