Hepatic lipid accumulation in apolipoprotein C-I-deficient mice is potentiated by cholesteryl ester transfer protein

Thomas Gautier,Uwe J.F Tietge,Renze Boverhof,Frank G Perton,Naig Le Guern,David Masson,Patrick C.N Rensen,Louis M Havekes,Laurent Lagrost,Folkert Kuipers

doi:10.1194/jlr.m600205-jlr200

Abstract

The impact of apolipoprotein C-I (apoC-I) deficiency on hepatic lipid metabolism was addressed in mice in the presence or the absence of cholesteryl ester transfer protein (CETP). In addition to the expected moderate reduction in plasma cholesterol levels, apoCIKO mice showed significant increases in the hepatic content of cholesteryl esters (+58%) and triglycerides (+118%) and in biliary cholesterol concentration (+35%) as compared with wild-type mice. In the presence of CETP, hepatic alterations resulting from apoC-I deficiency were enforced, with up to 58% and 302% increases in hepatic levels of cholesteryl esters and triglycerides in CETPTg/apoCIKO mice versus CETPTg mice, respectively. Biliary levels of cholesterol, phospholipids, and bile acids were increased by 88, 77, and 20%, respectively, whereas total cholesterol, HDL cholesterol, and triglyceride concentrations in plasma were further reduced in CETPTg/apoCIKO mice versus CETPTg mice. Finally, apoC-I deficiency was not associated with altered VLDL production rate. In line with the previously recognized inhibition of lipoprotein clearance by apoC-I, apoC-I deficiency led to decreased plasma lipid concentration, hepatic lipid accumulation, and increased biliary excretion of cholesterol. The effect was even greater when the alternate reverse cholesterol transport pathway via VLDL/LDL was boosted in the presence of CETP.

Highlights

The impact of apolipoprotein C-I deficiency on hepatic lipid metabolism was addressed in mice in the presence or the absence of cholesteryl ester transfer protein (CETP)
No significant differences were observed in plasma concentrations of free cholesterol and triglycerides, which are mainly confined to the VLDL fraction, in both wildtype and apoC-I knock-out mice (apoCIKO) mice
The present work reports for the first time a profound effect of apolipoprotein C-I (apoC-I) deficiency on hepatic lipid metabolism in mice. These effects were enforced in the presence of the human CETP transgene, emphasizing the close interaction between CETP and apoC-I in the processes involved in plasma-derived lipid uptake by the liver

Summary

Introduction

The impact of apolipoprotein C-I (apoC-I) deficiency on hepatic lipid metabolism was addressed in mice in the presence or the absence of cholesteryl ester transfer protein (CETP). In the presence of CETP, hepatic alterations resulting from apoC-I deficiency were enforced, with up to 58% and 302% increases in hepatic levels of cholesteryl esters and triglycerides in CETPTg/apoCIKO mice versus CETPTg mice, respectively. Hepatic lipid accumulation in apolipoprotein C-I-deficient mice is potentiated by cholesteryl ester transfer protein. Previous studies in transgenic mice have shown that the presence of CETP increases hepatic cholesterol content [4, 5] This mechanism depends on the clearance capacities of the apoB-containing lipoproteins by the liver. This article is available online at http://www.jlr.org

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