High-level expression of ABCG5 and ABCG8 attenuates diet-induced hypercholesterolemia and atherosclerosis in Ldlr^-/- mice

Transgenic mice expressing human ABCG5 (G5) and ABCG8 (G8) have decreased fractional absorption and increased biliary secretion of cholesterol, but their plasma cholesterol levels are unchanged (males) or modestly reduced (females). To determine whether increased expression of G5 and G8 can ameliorate hypercholesterolemia in mice lacking LDL receptors (LDLRs), we examined the effects of G5G8 transgene expression on cholesterol metabolism and atherosclerosis in Ldlr^-/- mice. In chow-fed Ldlr^-/- mice, the G5G8 transgene reduced fractional absorption of dietary cholesterol by 50% and increased biliary cholesterol levels by 60% but did not affect plasma cholesterol levels. On a Western diet (21% fat, 0.2% cholesterol), G5G8 ^Tg; Ldlr^-/- mice had a 30% reduction in the level of hepatic cholesterol and 45% lower plasma cholesterol levels than the Ldlr ^-/- mice. After 6 months on the Western diet, the atherosclerotic lesion area in the aortic root and arch was ∼70% lower in the G5G8 ^Tg;Ldlr^-/- than in the Ldlr^-/- mice and was correlated with the plasma cholesterol levels. These results demonstrate that increased expression of G5 and G8 attenuates diet-induced hypercholesterolemia in Ldlr^-/- mice, resulting in a significant reduction in plasma levels of cholesterol and aortic atherosclerotic lesion area.