Tissue-Specific Induction of Intestinal ABCA1 Expression With a Liver X Receptor Agonist Raises Plasma HDL Cholesterol Levels

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Abstract
ABCA1 controls the rate-limiting step in HDL particle formation and is therefore an attractive molecular target for raising HDL levels and protecting against atherosclerosis. Intestinal ABCA1 significantly and independently contributes to plasma HDL cholesterol levels in mice, suggesting that induction of intestinal ABCA1 expression may raise plasma HDL cholesterol levels. We evaluated the ability of a synthetic Liver X Receptor (LXR) agonist, GW3965, to raise plasma HDL cholesterol levels in control mice and mice with liver- or intestinal-specific deletion of the Abca1 gene. Oral treatment with GW3965 increased the expression of ABCA1 by ≈6-fold (P=0.004) as well as other LXR target genes in the intestines of mice, with no change in the hepatic expression of these genes. This resulted in a significant ≈48% elevation of plasma HDL cholesterol levels in wild-type mice (P<0.01) with no change in plasma triglycerides. A similar increase in HDL cholesterol was observed in mice lacking hepatic ABCA1, indicating that the increase in plasma HDL cholesterol was independent of hepatic ABCA1. This effect was completely abrogated in mice lacking intestinal ABCA1. These data indicate that intestinal ABCA1 may be an attractive therapeutic target for raising HDL levels while avoiding the hepatic lipogenesis and hypertriglyceridemia typical of systemic LXR activation.