Yangonin protects against estrogen–induced cholestasis in a farnesoid X receptor-dependent manner

Abstract Estrogen–induced cholestasis is a common etiology of hepatic diseases in women with contraceptives administration, pregnancy or hormone replacement therapy. Farnesoid X receptor (FXR) is a member of nuclear receptor super family of ligand-activated transcription factors that is highly expressed in liver. FXR is acknowledged to contribute to the bile acid homeostasis, as well as the pathogenesis and progression of cholestasis. Specific targeting of FXR is an innovative approach for the treatment of cholestasis. The current study aimed to verify the anti-cholestasis effect of yangonin that is a natural product isolated from Kava via FXR signaling pathway in vivo and in vitro. The analyses of FXR gain- or loss-of-function were performed. Yangonin treatment ameliorates estrogen-induced cholestasis through increasing bile flow and biliary bile acid output. The mechanisms were an induction in the hepatic efflux transporters (Bsep and Mrp2) and an inhibition in hepatic uptake transporter (Ntcp) by yangonin. Likewise, yangonin through repressing Cyp7a1, Cyp8b1 and inducing Sult2a1 expression suppressed bile acid synthesis and promoted bile acid metabolism. Furthermore, yangonin improved estrogen–induced inflammatory cell infiltration and the inflammation gene expression. In vitro experiments further consolidated that yangonin alleviated estrogen–caused cholestasis via FXR activation. Noteworthily, the effects of yangonin were enhanced by FXR expression plasmids but abrogated by FXR siRNA. In conclusion, yangonin alleviates estrogen–induced cholestasis, due to FXR-mediated gene regulation.