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.

E Reihnér,B Angelin,M Rudling,S Ewerth,I Björkhem,K Einarsson

doi:10.1016/s0022-2275(20)42109-1

E Reihnér, B Angelin + Show 4 more

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https://doi.org/10.1016/s0022-2275(20)42109-1

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Journal: Journal of Lipid Research	Publication Date: Dec 1, 1990
Citations: 122	License type: cc-by

Affiliation: Karolinska Institutet

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.

Highlights

IntroductionThere was a good correlation between hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity and low density lipoprotein (LDL) receptor binding (r, = +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
* lase more than sixfold, and increased both hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity (552 60 pmol/min per mg protein vs 103 f 9 pmol/min per mg protein) and low density lipoprotein (LDL) receptor expression (6.1 k 0.8 ng/mg protein; n = 6 vs 2.2 f 0.3 ng/mg protein; n = 7)
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. -ReihnCr, E., B

Summary

Introduction

There was a good correlation between HMG-CoA reductase activity and LDL receptor binding (r, = +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. The pool of bile acids recirculates several times daily, only small amounts ( = 1 mmol) being lost and excreted with the feces per day This loss is compensated for by de novo synthesis, and the production rate is controlled by feedback regulation exerted on the rate-limiting enzyme, cholesterol 7a-hydroxylase [2, 4]. The results indicate that in human liver, a parallel stimulation of HMG-CoA reductase activity and LDL receptor expression occurs in response to interruption of the enterohepatic circulation of bile acids ;> Does cholestyramine treatment increase the activity of HMG-CoA reductase, and, if so, is this achieved by enhancing the proportion of active enzyme? ;> Does the stimulation of LDL receptor expression occur independently or is it related to the changes induced in HMG-CoA reductase activity? and iii) Does age affect the capacity to increase cholesterol 7a-hydroxylase or HMG-CoA reductase activity in response to cholestyramine therapy? The results indicate that in human liver, a parallel stimulation of HMG-CoA reductase activity and LDL receptor expression occurs in response to interruption of the enterohepatic circulation of bile acids

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