Tissue-Specific Roles of ABCA1 Influence Susceptibility to Atherosclerosis

<jats:p> <jats:bold> <jats:italic>Objective—</jats:italic> </jats:bold> The ATP-binding cassette transporter, subfamily A, member 1 ( <jats:italic>ABCA1</jats:italic> ) plays a key role in HDL cholesterol metabolism. However, the role of <jats:italic>ABCA1</jats:italic> in modulating susceptibility to atherosclerosis is controversial. </jats:p> <jats:p> <jats:bold> <jats:italic>Methods and Results—</jats:italic> </jats:bold> We investigated the role of <jats:italic>ABCA1</jats:italic> in atherosclerosis using a combination of overexpression and selective deletion models. First, we examined the effect of transgenic overexpression of a full-length human <jats:italic>ABCA1</jats:italic> -containing bacterial artificial chromosome (BAC) in the presence or absence of the endogenous mouse <jats:italic>Abca1</jats:italic> gene. <jats:italic>ABCA1</jats:italic> overexpression in the atherosclerosis-susceptible <jats:italic>Ldlr</jats:italic> <jats:sup>−/−</jats:sup> background significantly reduced the development of atherosclerosis in both the presence and absence of mouse <jats:italic>Abca1</jats:italic> . Next, we used mice with tissue-specific inactivation of <jats:italic>Abca1</jats:italic> to dissect the discrete roles of <jats:italic>Abca1</jats:italic> in different tissues on susceptibility to atherosclerosis. On the <jats:italic>Apoe</jats:italic> <jats:sup>−/−</jats:sup> background, mice lacking hepatic <jats:italic>Abca1</jats:italic> had significantly reduced HDL cholesterol and accelerated atherosclerosis, indicating that the liver is an important site at which <jats:italic>Abca1</jats:italic> plays an antiatherogenic role. In contrast, mice with macrophage-specific inactivation of <jats:italic>Abca1</jats:italic> on the <jats:italic>Ldlr</jats:italic> <jats:sup>−/−</jats:sup> background displayed no change in atherosclerotic lesion area. </jats:p> <jats:p> <jats:bold> <jats:italic>Conclusions—</jats:italic> </jats:bold> These data indicate that physiological expression of <jats:italic>Abca1</jats:italic> modulates the susceptibility to atherosclerosis and establish hepatic <jats:italic>Abca1</jats:italic> expression as an important site of atheroprotection. In contrast, we show that selective deletion of macrophage <jats:italic>Abca1</jats:italic> does not significantly modulate atherogenesis. </jats:p>