Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8

Liqing Yu,Klaus Von Bergmann,Dieter Lütjohann,Helen H Hobbs,Jonathan C Cohen

doi:10.1194/jlr.m500124-jlr200

Abstract

The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile. Humans and mice lacking G5 and G8 (G5G8-/-) accumulate plant sterols in the blood and tissues. However, despite impaired biliary cholesterol secretion, plasma and liver cholesterol levels are lower in G5G8-/- mice than in wild-type littermates. To determine whether the observed changes in hepatic sterol metabolism were a direct result of decreased biliary sterol secretion or a metabolic consequence of the accumulation of dietary noncholesterol sterols, we treated G5G8-/- mice with ezetimibe, a drug that reduces the absorption of both plant- and animal-derived sterols. Ezetimibe feeding for 1 month sharply decreased sterol absorption and plasma levels of sitosterol and campesterol but increased cholesterol in both the plasma (from 60.4 to 75.2 mg/dl) and the liver (from 1.1 to 1.87 mg/g) of the ezetimibe-treated G5G8-/- mice. Paradoxically, the increase in hepatic cholesterol was associated with an increase in mRNA levels of HMG-CoA reductase and synthase. Together, these results indicate that pharmacological blockade of sterol absorption can ameliorate the deleterious metabolic effects of plant sterols even in the absence of G5 and G8.

Highlights

The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile
To determine whether the absence of G5 and G8 affected the magnitude of reduction in sterol absorption associated with ezetimibe treatment, we measured the fractional absorption of cholesterol, cholestanol, campesterol, and sitosterol in G5G8Ϫ/Ϫ mice after 1 month of treatment with ezetimibe
The major finding of this study is that the suppression of hepatic cholesterol synthesis in G5G8Ϫ/Ϫ mice is largely ameliorated by blocking the intestinal absorption of sterols with ezetimibe

Summary

Introduction

The ATP binding cassette transporters ABCG5 (G5) and ABCG8 (G8) limit the accumulation of neutral sterols by restricting sterol uptake from the intestine and promoting sterol excretion into bile. To determine whether the observed changes in hepatic sterol metabolism were a direct result of decreased biliary sterol secretion or a metabolic consequence of the accumulation of dietary noncholesterol sterols, we treated G5G8؊/؊ mice with ezetimibe, a drug that reduces the absorption of both plant- and animal-derived sterols. The increase in hepatic cholesterol was associated with an increase in mRNA levels of HMG-CoA reductase and synthase. Together, these results indicate that pharmacological blockade of sterol absorption can ameliorate the deleterious metabolic effects of plant sterols even in the absence of G5 and G8.—Yu, L., K. von Bergmann, D.

Methods

Results

Conclusion