出版社：American Society for Biochemistry and Molecular Biology
摘要：Previous studies in nonhuman primates revealed a striking positivecorrelation between liver cholesteryl ester (CE) secretion rateand the development of coronary artery atherosclerosis. CE incorporatedinto hepatic VLDL is necessarily synthesized by ACAT2, the cholesterol-esterifyingenzyme in hepatocytes. We tested the hypothesis that the levelof ACAT2 expression, in concert with cellular cholesterol availability,affects the CE content of apolipoprotein B (apoB)-containinglipoproteins. In a model system of lipoprotein secretion usingCOS cells cotransfected with microsomal triglyceride transferprotein and truncated forms of apoB, ACAT2 expression resultedin a 3-fold increase in microsomal ACAT activity and a 4-foldincrease in the radiolabeled CE content of apoB-lipoproteins.After cholesterol-cyclodextrin (Chol-CD) treatment, CE secretionwas increased by 27-fold in ACAT2-transfected cells but by only7-fold in control cells. Chol-CD treatment also caused the percentageof CE in the apoB-lipoproteins to increase from 3% to 33% incontrol cells and from 16% to 54% in ACAT2-transfected cells.In addition, ACAT2-transfected cells secreted 3-fold more apoBthan control cells. These results indicate that under all conditionsof cellular cholesterol availability tested, the relative levelof ACAT2 expression affects the CE content and, hence, the potentialatherogenicity, 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
