title: Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients.
abstract: To characterize the metabolic regulatory response to interruption of the enterohepatic circulation of bile acids, we examined the effects of cholestyramine treatment on the rate-limiting steps in cholesterol biosynthesis (HMG-CoA reductase) and bile acid production (cholesterol 7 alpha-hydroxylase) as well as on the heparin-sensitive binding of low density lipoproteins (LDL) (reflecting LDL receptor expression) in human liver. Altogether, 18 normolipidemic patients with uncomplicated cholesterol gallstone disease were treated with cholestyramine (8 g b.i.d.) for 2-3 weeks prior to cholecystectomy, and another 34 cholesterol gallstone patients served as untreated controls. Cholestyramine treatment stimulated cholesterol 7 alpha-hydroxylase more than sixfold, and increased both HMG-CoA reductase activity (552 +/- 60 pmol/min per mg protein vs 103 +/- 9 pmol/min per mg protein) and LDL receptor expression (6.1 +/- 0.8 ng/mg protein; n = 6 vs 2.2 +/- 0.3 ng/mg protein; n = 7). Moreover, there was a good correlation between HMG-CoA reductase activity and LDL receptor binding (rs = +0.71; n = 13), suggesting a simultaneous stimulatory effect to compensate for the increased hepatic cholesterol catabolism due to bile acid depletion caused by cholestyramine. Further evidence for this assumption was the finding of a significant relationship between cholesterol 7 alpha-hydroxylase activity and both LDL receptor expression (rs = +0.77; n = 13) and HMG-CoA reductase activity (rs = +0.76; n = 46). We conclude that in human liver a parallel stimulation of cholesterol synthesis and LDL receptor expression occurs in response to stimulation of bile acid synthesis.
authors.affiliation: Department of Surgery, Karolinska Institutet, Huddinge University Hospital, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Reihnér
authors.forename: B
authors.initials: B
authors.lastname: Angelin
authors.forename: M
authors.initials: M
authors.lastname: Rudling
authors.forename: S
authors.initials: S
authors.lastname: Ewerth
authors.forename: I
authors.initials: I
authors.lastname: Björkhem
authors.forename: K
authors.initials: K
authors.lastname: Einarsson
mesh_terms: D000328:Adult; D000368:Aged; D002769:Cholelithiasis / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D002792:Cholestyramine Resin / Q000494:pharmacology*; D005260:Female; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008875:Middle Aged
chemical_list: D008077:Lipoproteins, LDL; D002792:Cholestyramine Resin; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases