Abstract-Mutations in ATP-binding cassette transporter A1 (ABCA1) cause Tangier disease and familial hypoalphalipoproteinemia, resulting in low to absent plasma high-density lipoprotein cholesterol levels. However, wide variations in clinical lipid phenotypes are observed in patients with mutations in ABCA1. We hypothesized that the various lipid phenotypes would be the direct result of discrete and differing effects of the mutations on ABCA1 function. To determine whether there is a correlation between the mutations and the resulting phenotypes, we generated in vitro 15 missense mutations that have been described in patients with Tangier disease and familial hypoalphalipoproteinemia. Using localization of ABCA1, its ability to induce cell surface binding of apolipoprotein A-I, and its ability to elicit efflux of cholesterol and phospholipids to apolipoprotein A-I we determined that the phenotypes of patients correlate with the severity and nature of defects in ABCA1 function. (Circ Res. 2006;99:389-397.)

Changes in cellular cholesterol affect insulin secretion, and β-cell–specific deletion or loss-of-function mutations in the cholesterol efflux transporter ATP-binding cassette transporter A1 (ABCA1) result in impaired glucose tolerance and β-cell dysfunction. Upregulation of ABCA1 expression may therefore be beneficial for the maintenance of normal islet function in diabetes. Studies suggest that microRNA-33a (miR-33a) expression inversely correlates with ABCA1 expression in hepatocytes and macrophages. We examined whether miR-33a regulates ABCA1 expression in pancreatic islets, thereby affecting cholesterol accumulation and insulin secretion. Adenoviral miR-33a overexpression in human or mouse islets reduced ABCA1 expression, decreased glucose-stimulated insulin secretion, and increased cholesterol levels. The miR-33a–induced reduction in insulin secretion was rescued by cholesterol depletion by methyl-β-cyclodextrin or mevastatin. Inhibition of miR-33a expression in apolipoprotein E knockout islets and ABCA1 overexpression in β-cell–specific ABCA1 knockout islets rescued normal insulin secretion and reduced islet cholesterol. These findings confirm the critical role of β-cell ABCA1 in islet cholesterol homeostasis and β-cell function and highlight modulation of β-cell miR-33a expression as a means to influence insulin secretion.

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...