FXR Activation Increases Reverse Cholesterol Transport by Modulating Bile Acid Composition and Cholesterol Absorption

Activation of farnesoid X receptor (FXR) markedly attenuates the development of atherosclerosis in animal models. However, the underlying mechanism is not well elucidated. Here we show that the FXR agonist obeticholic acid (OCA) increases fecal cholesterol excretion and macrophage reverse cholesterol transport (RCT) dependent on activation of hepatic FXR. OCA does not increase biliary cholesterol secretion but inhibits intestinal cholesterol absorption. OCA markedly inhibits hepatic cholesterol 7α-hydroxylase (Cyp7a1) and sterol 12α-hydroxylase (Cyp8b1) partly through inducing small heterodimer partner (Shp), leading to reduced bile acid pool size and altered bile acid composition, with the α/β-muricholic acid proportion in the bile increased by 2.6 fold and taurocholic acid (TCA) level reduced by 71%. Over-expression of Cyp8b1 or concurrent over-expression of Cyp7a1 and Cyp8b1 normalizes TCA level, bile acid composition and intestinal cholesterol absorption. Conclusions: Our data indicate that activation of FXR inhibits intestinal cholesterol absorption via modulation of bile acid pool size and composition, thus leading to increased RCT. Targeting hepatic FXR and/or bile acids may be useful for boosting RCT and preventing the development of atherosclerosis. This article is protected by copyright. All rights reserved.