Cholesterol synthesis inhibition elicits an integrated molecular response in human livers including decreased ACAT2

Abstract

Objective: The purpose of this study was to identify how different degrees of cholesterol synthesis inhibition affect human hepatic cholesterol metabolism.

Methods and results: Thirty-seven normocholesterolemic gallstone patients randomized to treatment with placebo, 20 mg/d fluvastatin, or 80 mg/d atorvastatin for 4 weeks were studied. Based on serum lathosterol determinations, cholesterol synthesis was reduced by 42% and 70% in the 2 groups receiving statins. VLDL cholesterol was reduced by 20% and 55%. During gallstone surgery, a liver biopsy was obtained and hepatic protein and mRNA expression of rate-limiting steps in cholesterol metabolism were assayed and related to serum lipoproteins. A marked induction of LDL receptors and 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase was positively related to the degree of cholesterol synthesis inhibition (ChSI). The activity, protein, and mRNA for ACAT2 were all reduced during ChSI, as was apoE mRNA. The lowering of HDL cholesterol in response to high ChSI could not be explained by altered expression of the HDL receptor CLA-1, ABCA1, or apoA-I.

Conclusions: Statin treatment reduces ACAT2 activity in human liver and this effect, in combination with a reduced Apo E expression, may contribute to the favorable lowering of VLDL cholesterol seen in addition to the LDL lowering during statin treatment.

Figure 1

Effects of ChSI on hepatic cholesterol metabolism. Percent reduction from baseline levels (see Table 1) in plasma total cholesterol (A) and in plasma lathosterol/cholesterol ratio (B); LDL receptor activity (C); LDL receptor mRNA (D); HMG CoA reductase mRNA (E); and SREBP-2 mRNA (F). Data show mean + SEM. *, p<0.05; ***, p<0.001. For details please see www.ahajornals.org

Figure 2

Effects of ChSI on plasma lipoprotein cholesterol profiles. Gray solid line, lipoprotein cholesterol profiles before treatment; black solid line, cholesterol lipoprotein profiles after treatment. Insets show % variation from baseline levels of the area-under-the-curve for each lipoprotein fraction. Data show mean ± SEM. **, p<0.01; ***, p<0.001. For details please see www.ahajornals.org

Figure 3

Effects of ChSI on hepatic ACAT2 and Apo E expression. A) ACAT2 activity in pooled liver microsomes; B) ACAT2 protein expression in pooled liver microsomes.; C) hepatic ACAT2 mRNA levels in individual mRNA preparations; D) apo E mRNA in individual mRNA preparations. Data show mean + SEM when individual samples were assayed. *, p<0.05. For details please see www.ahajornals.org

Figure 4

Effects of ChSI on hepatic CLA-I and ABCG8 protein expression. Liver membrane proteins were loaded and separated on SDS/PAGE. After transfer onto nitrocellulose filter, samples were incubated with either A) anti-mouse SR-BI, reactive to human CLA-I, or B) with anti-human ABCG8 antibody. Data show mean ± SEM. *, p<0.05. For details please see www.ahajornals.org