Hepatocellular 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. We used the farnesoid X receptor knockout (KO) mouse model to study bile acid-dependent HCC. Temporal tracking of circulating bile acids determined more than 80% of KO females developed spontaneous cholemia (ie, serum total bile acids ≥40 μmol/L) as early as 8 weeks old. Opposingly, KO males were highly resistant to cholemia, with ∼23% incidence even when 26 weeks old. However, KO males demonstrated higher levels of deoxycholate than females. Compared with males, KO females had more severe cholestatic liver injury and further aberrancies in bile acid metabolism. Yet, KO 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 KO females. Despite higher cholemia prevalence in KO females, their tumor burden was less compared with KO males. An exception to this sex-dimorphic pattern was found in a subset of male and female KO mice born with congenital cholemia due to portosystemic shunt, where both sexes had comparable robust HCC. Our study highlights bile acids as sex-dimorphic metabolites in HCC except in the case of portosystemic shunt.

中文翻译：

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胆汁酸代谢对小鼠肝癌的性别二态性影响

肝细胞癌（HCC）是一种男性占主导地位的疾病，但靶向性激素治疗尚未成功。胆汁酸是一种潜在的肝癌致癌物，并且是具有类似激素作用的生物分子。一些研究强调了它们在生理学和疾病方面潜在的性别二态性。我们假设胆汁酸可能是解释肝癌性别差异的潜在分子特征。我们使用法尼醇 X 受体敲除 (KO) 小鼠模型来研究胆汁酸依赖性 HCC。循环胆汁酸的时间追踪确定，超过 80% 的 KO 雌性早在 8 周龄时就出现自发性胆汁酸（即血清总胆汁酸≥40 μmol/L）。相反，KO 雄性对胆血症具有高度抵抗力，即使在 26 周龄时，发病率也高达 23%。然而，KO 雄性的脱氧胆酸水平高于雌性。与男性相比，KO女性胆汁淤积性肝损伤更严重，胆汁酸代谢也出现进一步异常。然而，KO 雌性表达更多的解毒转录本，并且具有更多的胆汁酸肾脏排泄。干预 CYP7A1（胆汁酸生物合成限速酶）缺乏或补充牛磺酸，使胆汁酸水平完全或部分正常化，并导致 KO 女性肝损伤。尽管 KO 女性的胆血症患病率较高，但与 KO 男性相比，她们的肿瘤负担较小。这种性别二态性模式的一个例外是在雄性和雌性 KO 小鼠子集中发现的，这些小鼠由于门体分流而出生时患有先天性胆血症，其中两性都具有相当的强健 HCC。我们的研究强调胆汁酸在 HCC 中是性别二态代谢物，门体分流情况除外。