Accumulation of toxic
bile acids in liver could cause
cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of
yangonin, a product isolated from an edible botanical Kava against
lithocholic acid (LCA)-induced
cholestasis, and further to elucidate the involvement of farnesoid X receptor (FXR) in the anticholestatic effect using in vivo and in vitro experiments. The cholestatic liver injury model was established by
intraperitoneal injections of LCA in C57BL/6 mice. Serum
biomarkers and H&E staining were used to identify the amelioration of
cholestasis after
yangonin treatment. Mice hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying
yangonin hepatoprotection. The results indicated that
yangonin promoted
bile acid efflux and reduced hepatic uptake via an induction in FXR-target genes Bsep, Mrp2 expression and an inhibition in Ntcp, all of which are responsible for
bile acid transport. Furthermore,
yangonin reduced
bile acid synthesis through repressing FXR-target genes Cyp7a1 and
Cyp8b1, and increased
bile acid metabolism through an induction in gene expression of Sult2a1, which are involved in
bile acid synthesis and metabolism. In addition,
yangonin suppressed liver
inflammation through repressing
inflammation-related gene NF-κB, TNF-α and IL-1β. In vitro evidences showed that the changes in transporters and
enzymes induced by
yangonin were abrogated when FXR was silenced. In conclusions,
yangonin produces protective effect against LCA-induced hepatotoxity and
cholestasis due to FXR-mediated regulation.
Yangonin may be an effective approach for the prevention against cholestatic
liver diseases.