Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice

Abstract

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.

Efficient reabsorption of transintestinally excreted cholesterol is a strong determinant for cholesterol disposal in mice

“…Furthermore, the observations by Van der Velde et al are in contrast to those by De Boer et al who showed that using bile diverted rats that induction of TICE by intestinal FXR activation required a change of biliary bile acid composition towards a more hydrophilic profile (22). This is in line with another murine study using different FXR agonists and an earlier in vitro observation where UDCA was more efficient in promoting ABCG5/8 dependent cholesterol efflux than CA (47,48).…”

Farnesoid X receptor induces Takeda G-protein receptor 5 cross-talk to regulate bile acid synthesis and hepatic metabolism

“…OCA is known to inhibit bile acid synthesis and decrease the bile acid pool (28). INT-777 did not affect bile acid synthesis and pool size (22), whereas the effect of INT-767 on bile acid synthesis has not been studied.…”

Mechanisms of bile acid mediated inflammation in the liver

“…Treatment with obeticholic acid results in decreases in alkaline phosphatase, γ-glutamyl transpeptidase and alanine aminotransferase in PBC patients (108, 109). The anti-inflammtory effects of obeticholic acid in PBC patients are likely related to FXR mediated inhibition of cholesterol 7α-hydroxylase (CYP7A1) and a reduction in the bile acid pool (110). …”