Submitted on March 1, 2007
Accepted on April 16, 2007
ACAT2 stimulates cholesteryl ester secretion in ApoB-containing lipoproteins
Ryan E. Temel, Li Hou, Lawrence L. Rudel, and Gregory S. Shelness
Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1040
Corresponding Author: gshelnes{at}wfubmc.edu
Previous studies in non-human 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 acyl-CoA:cholesterol acyltransferase 2 (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 apoB-containing lipoproteins. In a model system of lipoprotein secretion utilizing COS cells cotransfected with MTP 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. Following 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.
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