Affiliation:
1. From the Departments of Medicine and Biochemistry and The John P. Robarts Research Institute, University of Western Ontario, London, Ontario, Canada (L.J.W., M.W.H.); the University of Washington, Seattle, WA (P.H.R.B.); and Parke-Davis Pharmaceutical Research, Warner Lambert Co, Ann Arbor, MI (R.S.N.).
Abstract
Abstract
—The concept that hepatic cholesteryl ester (CE) mass and the rate of cholesterol esterification regulate hepatocyte assembly and secretion of apoB-containing lipoproteins remains controversial. The present study was carried out in HepG2 cells to correlate the rate of cholesterol esterification and CE mass with apoB secretion by CI-1011, an acyl CoA:cholesterol acyltransferase (ACAT) inhibitor that is known to decrease apoB secretion, in vivo, in miniature pigs. HepG2 cells were incubated with CI-1011 (10 nmol/L, 1 μmol/L, and 10 μmol/L) for 24 hours. ApoB secretion into media was decreased by 25%, 27%, and 43%, respectively (
P
<0.0012). CI-1011 (10 μmol/L) inhibited HepG2 cell ACAT activity by 79% (
P
<0.002) and cellular CE mass by 32% (
P
<0.05). In contrast, another ACAT inhibitor, DuP 128 (10 μmol/L), decreased cellular ACAT activity and CE mass by 85% (
P
<0.002) and 42% (
P
=0.01), respectively, but had no effect on apoB secretion into media. To characterize the reduction in apoB secretion by CI-1011, pulse-chase experiments were performed and analyzed by multicompartmental modelling using SAAM II. CI-1011 did not affect the synthesis of apoB or albumin. However, apoB secretion into the media was decreased by 42% (
P
=0.019). Intracellular apoB degradation increased proportionately (
P
=0.019). The secretion of albumin and cellular reuptake of labeled lipoproteins were unchanged. CI-1011 and DuP 128 did not affect apoB mRNA concentrations. These results show that CI-1011 decreases apoB secretion by a mechanism that involves an enhanced intracellular degradation of apoB. This study demonstrates that ACAT inhibitors can exert differential effects on apoB secretion from HepG2 cells that do not reflect their efficacy in inhibiting cholesterol esterification.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
48 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献