ABCA1 overexpression leads to hyperalphalipoproteinemia and increased biliary cholesterol excretion in transgenic mice

The discovery of the ABCA1 lipid transporter has generated interest in modu lating human plasma HDL levels and atherogenic risk by enhancing ABCA1 gene expression. To determine if increased ABCA1 expression modulates HDL metab olism in vivo, we generated transgenic mice that overexpress human ABCA1 (h ABCA1-Tg). Hepatic and macrophage expression of hABCA1 enhanced macrophage cholesterol efflux to apoA-I; increased plasma cholesterol, cholesteryl est ers (CEs), free cholesterol, phospholipids, HDL cholesterol, and apoA-I and apoB levels; and led to the accumulation of apoE-rich HDL1. ABCA1 transgen e expression delayed I-125-apoA-I catabolism in both liver and kidney, lead ing to increased plasma apoA-I levels, but had no effect on apoB secretion after infusion of Triton WR1339. Although the plasma clearance of HDL-CE wa s not significantly altered in hABCA1-Tg mice, the net hepatic delivery of exogenous 3H-CEt-HDL, which is dependent on the HDL pool size, was increase d 1.5-fold. In addition, the cholesterol and phospholipid concentrations in hABCA1-Tg bile were increased 1.8-fold. These studies show that steady-sta te overexpression of ABCA1 in vivo (a) raises plasma apoB levels without al tering apoB secretion and (b) raises plasma HDL-C and apoA-I levels, facili tating hepatic reverse cholesterol transport and biliary cholesterol excret ion. Similar metabolic changes may modify atherogenic risk in humans.