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Originally published In Press as doi:10.1194/jlr.M700109-JLR200 on April 16, 2007

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Journal of Lipid Research, Vol. 48, 1618-1627, July 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

ACAT2 stimulates cholesteryl ester secretion in apoB-containing lipoproteins

Ryan E. Temel, Li Hou, Lawrence L. Rudel and Gregory S. Shelness1

Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157

Published, JLR Papers in Press, April 16, 2007.

1 To whom correspondence should be addressed. e-mail: gshelnes{at}wfubmc.edu

Previous studies in nonhuman primates revealed a striking positive correlation between liver cholesteryl ester (CE) secretion rate and the development of coronary artery atherosclerosis. CE incorporated into hepatic VLDL is necessarily synthesized by ACAT2, the cholesterol-esterifying enzyme in hepatocytes. We tested the hypothesis that the level of ACAT2 expression, in concert with cellular cholesterol availability, affects the CE content of apolipoprotein B (apoB)-containing lipoproteins. In a model system of lipoprotein secretion using COS cells cotransfected with microsomal triglyceride transfer protein and truncated forms of apoB, ACAT2 expression resulted in a 3-fold increase in microsomal ACAT activity and a 4-fold increase in the radiolabeled CE content of apoB-lipoproteins. After cholesterol-cyclodextrin (Chol-CD) treatment, CE secretion was increased by 27-fold in ACAT2-transfected cells but by only 7-fold in control cells. Chol-CD treatment also caused the percentage of CE in the apoB-lipoproteins to increase from 3% to 33% in control cells and from 16% to 54% in ACAT2-transfected cells. In addition, ACAT2-transfected cells secreted 3-fold more apoB than control cells. These results indicate that under all conditions of cellular cholesterol availability tested, the relative level of ACAT2 expression affects the CE content and, hence, the potential atherogenicity, of nascent apoB-containing lipoproteins.

Supplementary key words atherosclerosis • lipid mobilization • lipoprotein assembly • very low density lipoprotein • apolipoprotein B • triglycerides • acyl-coenzyme A:cholesterol acyltransferase 2

Abbreviations: AP, alkaline phosphatase; apoB, apolipoprotein B; CD, methyl-ß-cyclodextrin; CE, cholesteryl ester; Chol-CD, free cholesterol solubilized in methyl-ß-cyclodextrin; LDLr, low density lipoprotein receptor; MTP, microsomal triglyceride transfer protein; PL, phospholipid; TG, triglyceride


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