title: 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 flbroblasts from patients. Hepatic HMG-CoA reductase activities in patients were decreased 76% (P < .05) as compared with results in control subjects. In contrast, HMG-CoA reductase activities in sitosterolemic fibroblasts were not decreased as compared with results in control fibroblasts, and the activities in all cells were up-regulated similarly when they were exposed to delipidated medium. Because the cultured sitosterolemic fibroblasts contained only trace amounts of plant sterols, we added 20 microg/mL sitosterol directly to the cell medium. Raising the intracellular sitosterol concentration to 7% of cellular cholesterol level increased HMG-CoA reductase activity 23% (P < .05), while the addition of the same amount of cholesterol to the cells reduced the activity 46% (P < .05). Thus, when sitosterolemic skin fibroblasts were used, it was possible to distinguish between the effects of cholesterol and those of sitosterol on the activity of HMG-CoA reductase. These results suggest that reduced HMG-CoA reductase activity in this disease is caused by secondary effects of unknown regulator(s) other than sitosterol.
authors.affiliation: Department of Gastroenterology, University of Tsukuba, Tsukuba City, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Honda
authors.forename: G
authors.initials: G
authors.lastname: Salen
authors.forename: M
authors.initials: M
authors.lastname: Honda
authors.forename: A K
authors.initials: AK
authors.lastname: Batta
authors.forename: G S
authors.initials: GS
authors.lastname: Tint
authors.forename: G
authors.initials: G
authors.lastname: Xu
authors.forename: T S
authors.initials: TS
authors.lastname: Chen
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Shefer
mesh_terms: D000293:Adolescent; D000328:Adult; D001013:Aorta, Thoracic; D001161:Arteriosclerosis / Q000201:enzymology; D002478:Cells, Cultured; D002784:Cholesterol / Q000494:pharmacology*; D005260:Female; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000201:enzymology*; D008297:Male; D012016:Reference Values; D012855:Sitosterols / Q000097:blood* / Q000494:pharmacology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012855:Sitosterols; C025473:gamma-sitosterol; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases