Farnesoid X receptor contributes to oleanolic acid‐induced cholestatic liver injury in mice

Abstract

Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug-induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a longterm use. The present study aimed to investigate the role of FXR in OA-induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR À/À ) mice. The results showed that a significant alleviation in OA-induced cholestatic liver injury was observed in FXR À/À mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC-MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR À/À mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR À/À mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR À/À mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA-induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.

AMP‐activated protein kinase‐farnesoid X receptor pathway contributes to oleanolic acid‐induced liver injury

“…This hypothesis has obtained support of numerous studies, and the FXR agonist GW4064 was shown to attenuate cholestasis in rat (Liu et al, 2003). On the other hand, contrary to the intuition, the FXR knockout mice have attenuated liver injury in obstructive cholestasis models (Stedman et al, 2006), knockout of FXR protects mice from cholestatic liver injury induced by OA (Feng et al, 2022), and obeticholic acid (OCA)‐induced FXR activation exacerbates liver injury (Carino et al, 2020). These researches clearly demonstrate that FXR has different effects in different situations and other mechanisms may be also associated with FXR‐mediated cholestatic liver injury.…”

Oleanolic Acid Inhibits SCD1 Gene Expression to Ameliorate Fructose‐Induced Hepatosteatosis through SREBP1c‐Dependent and ‐Independent Mechanisms

“…[ 37 ] OA‐treated mice received 75 mg kg −1 OA by gavage once every day based on previous reports and the pre‐experimental results. [ 41,42 ] According to the U.S. Food and Drug Administration, the animal dose must be extrapolated to humans by normalizing to the body surface area. [ 43 ] The administered dose of OA in rats was consistent with the 250 mg day −1 dose for a 60‐kg adult human.…”