Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis

Abstract

Objective-The ATP-binding cassette transporter, subfamily A, member 1 (ABCA1) plays a key role in HDL cholesterol metabolism. However, the role of ABCA1 in modulating susceptibility to atherosclerosis is controversial. Methods and Results-We investigated the role of ABCA1 in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human ABCA1-containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse Abca1 gene. ABCA1 overexpression in the atherosclerosis-susceptible Ldlr Ϫ/Ϫ background significantly reduced the development of atherosclerosis in both the presence and absence of mouse Abca1. Next, we used mice with tissue-specific inactivation of Abca1 to dissect the discrete roles of Abca1 in different tissues on susceptibility to atherosclerosis. On the Apoe Ϫ/Ϫ background, mice lacking hepatic Abca1 had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which Abca1 plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of Abca1 on the Ldlr Ϫ/Ϫ background displayed no change in atherosclerotic lesion area. Conclusions-These data indicate that physiological expression of Abca1 modulates the susceptibility to atherosclerosis and establish hepatic Abca1 expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage Abca1 does not significantly modulate atherogenesis. Key Words: lipid and lipoprotein metabolism Ⅲ genetically altered mice Ⅲ pathophysiology of atherosclerosis T he ATP binding cassette transporter, subfamily A, member 1 (ABCA1) regulates the rate-limiting step in the biogenesis of high-density lipoprotein (HDL) particles by mediating the efflux of cellular cholesterol and phospholipids to apolipoprotein A-I (apoA-I) and therefore plays a critical role in reverse cholesterol transport. 1 Mutations in ABCA1 in humans cause Tangier disease (TD), characterized by nearly absent HDL cholesterol and lipid accumulation in tissue macrophages. Several recent genome-wide association studies have identified common variants in ABCA1 as a significant source of variation in plasma HDL cholesterol levels across multiple ethnic groups, 2-4 establishing ABCA1 as a major gene influencing HDL levels in humans.Despite the known role of ABCA1 in determining plasma HDL levels, the impact of ABCA1 on atherosclerosis remains controversial and incompletely understood. TD patients have increased risk of coronary artery disease relative to related controls, 5,6 though perhaps not as great a risk as would be expected based on their extremely low HDL cholesterol levels. In contrast, a recent study suggested that low HDL caused by loss-of-function mutations in ABCA1 does not contribute to risk of cardiovascular disease in the general population. 7 Studies in mouse models have also yielded conflicting results. Mice lacking Abca1 globally exhi...

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

“…These mice also displayed increased plasma TG concentrations, perhaps due to a small but significantly delayed clearance of plasma VLDL particles caused by their cholesterol enrichment. However, a more modest overexpression of ABCA1 protein (ϳ25%) using the endogenous ABCA1 promoter in LDLrKO mice resulted in no significant increase in apoB-containing lipoprotein concentration and a significant reduction in atherosclerosis, probably due to an increase in macrophage ABCA1 protein expression (45). The reasons for the apparently discrepant impact of ABCA1 overexpression on LDL concentrations and atherosclerosis in LDLrKO mice are 2-fold.…”

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).…”

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

“…Although passive diffusion plays a minor role, active transport via several transporters is responsible for the bulk of the efflux of cholesterol from macrophages into the serum; this process includes the transport to lipid-poor ApoA1 or HDL by ABCA1 and ABCG1 (Adorni et al, 2007). Although the selective deletion of ABCA1 in macrophages (Brunham et al, 2009) and the overexpression of ABCG1 (Burgess et al, 2008) did not significantly modulate the development of atherosclerotic plaques, simultaneous deficiency in both ABCA1 and ABCG1 promoted atherosclerosis in mice (Yvan-Charvet et al, 2007). In addition to ABCA1 and ABCG1, SR-BI, another type B scavenger receptor, protects against atherosclerosis when expressed in macrophages by stimulating cholesterol efflux, whereas genetically suppressing SR-BI activity in ApoE-deficient mice dramatically accelerates the onset of atherosclerosis (Trigatti et al, 1999).…”