Circulating bile acid levels direct sex-differences in liver cancer development

Hepatocellular carcinoma (HCC) is the most common liver cancer with a higher incidence in males. Here, we report that the spontaneous HCC development subsequent to the deletion of both Farnesoid X Receptor and Small Heterodimer Partner (DKO) mimics the sex-specific incidence seen clinically. In female DKO mice, we find lower levels of circulating bile acids (BA) and show that BAs can co-opt the estrogen axis to auto-regulate their homeostasis and amino acid metabolism. These regulations are lost when female mice are ovariectomized. Conversely, increasing serum BA levels is sufficient to promote tumorigenesis in female livers. To examine the translational relevance, we mined the transcriptomic signatures corresponding to that of female mice and found that it correlated well with those of low-grade tumors and associated with better outcomes for HCC patients. We demonstrate that decreasing enterohepatic recirculation of BAs using a resin dramatically reduced the liver cancer burden in male mice. These results uncover that sexual dimorphism in liver cancer incidence is linked to sex-differences in the handling of circulating BA concentrations and that lowering it might alleviate liver cancer.SignificanceWe demonstrate that serum BA concentration facilitates sex-differences in tumor burden, with reduced BA levels resulting in lower HCC risk in female mice. Increasing or decreasing circulating BA levels, promotes or alleviates HCC risk, respectively. We show that the sex-specific gene profiles identified in the DKO mice model of HCC correlate directly with patient outcomes.