ABCA1 Overexpression in the Liver of LDLr-KO Mice Leads to Accumulation of Pro-atherogenic Lipoproteins and Enhanced Atherosclerosis

Abstract

The identification of ABCA1 as a key transporter responsible for cellular lipid efflux has led to considerable interest in defining its role in cholesterol metabolism and atherosclerosis. In this study, the effect of overexpressing ABCA1 in the liver of LDLr-KO mice was investigated. Compared with LDLr-KO mice, ABCA1-Tg ؋ LDLr-KO (ABCA1-Tg) mice had significantly increased plasma cholesterol levels, mostly because of a 2.8-fold increase in cholesterol associated with a large pool of apoB-lipoproteins. ApoB synthesis was unchanged but the catabolism of 125 I-apoB-VLDL and -LDL were significantly delayed, accounting for the 1.35-fold increase in plasma apoB levels in ABCA1-Tg mice. We also found rapid in vivo transfer of free cholesterol from HDL to apoB-lipoproteins in ABCA1-Tg mice, associated with a significant 2.7-fold increase in the LCAT-derived cholesteryl linoleate content found primarily in apoB-lipoproteins. ABCA1-Tg mice had 1.4-fold increased hepatic cholesterol concentrations, leading to a compensatory 71% decrease in de novo hepatic cholesterol synthesis, as well as enhanced biliary cholesterol, and bile acid secretion. CAV-1, CYP2b10, and ABCG1 were significantly induced in ABCA1-overexpressing livers; however, no differences were observed in the hepatic expression of CYP7␣1, CYP27␣1, or ABCG5/G8 between ABCA1-Tg and control mice. As expected from the pro-atherogenic plasma lipid profile, aortic atherosclerosis was increased 10-fold in ABCA1-Tg mice. In summary, hepatic overexpression of ABCA1 in LDLr-KO mice leads to: 1) expansion of the pro-atherogenic apoB-lipoprotein cholesterol pool size via enhanced transfer of HDL-cholesterol to apoB-lipoproteins and delayed catabolism of cholesterol-enriched apoB-lipoproteins; 2) increased cholesterol concentration in the liver, resulting in up-regulated hepatobiliary sterol secretion; and 3) significantly enhanced aortic atherosclerotic lesions.

Enhanced vascular permeability facilitates entry of plasma HDL and promotes macrophage-reverse cholesterol transport from skin in mice

“…Thus, we can only speculate that high m-RCT rates in the LDLr-defi cient mice ( Fig. 7C ) might have been caused by an enhanced passage of plasma HDL through the skin followed by an alternative m-RCT route that includes transfer of cholesterol to LDL and uptake of the cholesterol-enriched LDL by the hepatic LRP receptor ( 42 ). In addition, effl ux of macrophage cholesterol to LDL could predominate when its concentration exceeds that of HDL ( 43 ).…”

Inhibition of ERK1/2 and Activation of Liver X Receptor Synergistically Induce Macrophage ABCA1 Expression and Cholesterol Efflux

“…In contrast, overexpression of ABCA1 leads to increased macrophage free cholesterol efflux, improved plasma lipid profiles, and reduced lesions in proatherogenic mice (6,17,35,36). Interestingly, alteration of ABCA1 expression tissue specifically leads to different observations: 1) either overexpression or inactivation of hepatic ABCA1 can lead to the development of atherosclerosis (37,38) and 2) activation of macrophage ABCA1 can inhibit atherosclerosis, whereas inactivation of macrophage ABCA1 can increase atherosclerosis (18,37,39).…”

Targeted Deletion of Hepatocyte ABCA1 Leads to Very Low Density Lipoprotein Triglyceride Overproduction and Low Density Lipoprotein Hypercatabolism

“…Transgenic LDLrKO mice with 2.3-fold overexpression of ABCA1 protein in the liver displayed significantly increased plasma VLDL, LDL, and HDL cholesterol concentrations, increased apoA-I and apoB levels, delayed clearance of VLDL and LDL tracers, and an increase in atherosclerosis (44). These data led to the hypothesis that liver ABCA1 may play a proatherogenic role in vivo, resulting from its dramatic effects on the metabolism of apoB-containing lipoproteins.…”