Sex Dimorphic Effects of Bile Acid Metabolism in Liver Cancer in Mice

Abstract

Background & AimsHepatocellular carcinoma (HCC) is a male-dominant disease, but targeted sex hormone therapies have not been successful. Bile acids are a potential liver carcinogen and are biomolecules with hormone-like effects. A few studies highlight their potential sex dimorphism in physiology and disease. We hypothesized that bile acids could be a potential molecular signature that explains sex disparity in HCC. Approach & ResultsWe employed the farnesoid X receptor knockout (FxrKO) mouse model to study bile acid-dependent HCC. Temporal tracking of circulating bile acids determined over 80% of FxrKO females developed spontaneous cholemia (i.e., serum total bile acids ≥40 μM) as early as 8 weeks old. Opposingly, FxrKO males were highly resistant to cholemia with ∼23% incidence even when 26 weeks old. Yet, FxrKO males demonstrated higher levels of deoxycholate than females. Compared to males, FxrKO females had more severe cholestatic liver injury and further aberrancies in bile acid metabolism. Yet, FxrKO females expressed more detoxification transcripts and had greater renal excretion of bile acids. Intervention with CYP7A1 (rate limiting enzyme for bile acid biosynthesis) deficiency or taurine supplementation either completely or partially normalized bile acid levels and liver injury in FxrKO females. Despite higher cholemia prevalence in FxrKO females, their tumor burden was less compared to FxrKO males. An exception to this sex-dimorphic pattern was found in a subset of male and female FxrKO mice born with congenital cholemia due to portosystemic shunt, where both sexes had comparable robust HCC. ConclusionsOur study highlights bile acids as sex-dimorphic metabolites in HCC except in the case of portosystemic shunt.