Sex differences in bile acid homeostasis and excretion underlie the disparity in liver cancer incidence between males and females

• DOI: 10.7554/elife.96783.1
• Publication Date: 2024-07-18T11:25:16Z
• Authors: Megan E Patton; Sherwin Kelekar; Lauren J Taylor; Angela E Dean; Qianying Zuo; Rhishikesh N Thakare; Sung Hwan Lee; Emily Gentry; Morgan Panitchpakdi; Pieter Dorrestein; Yazen Alnouti; Zeynep Madak-Erdogan; Ju-Seog Lee; Milton J Finegold; Sayeepriyadarshin...
• Keywords: Liver Cancer; Farnesoid X receptor; Enterohepatic circulation; Small heterodimer partner; Knockout mouse

Hepatocellular carcinoma (HCC), the most common liver cancer, exhibits a higher incidence in males. Here, we report that mice lacking bile acid regulators, Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP), recapitulate sex difference cancer risk. Since few therapeutic options are available, focused on understanding intrinsic protection afforded to female livers. Transcriptomic analysis control FXR SHP double knockout livers identified female-specific changes metabolism, including amino acids, lipids steroids. We examined if obtained transcriptomic signatures correlate with survival outcomes for HCC patients assess translational potential of this murine model. Gene signature is unique females correspond low-grade tumors better survival. Ovariectomy blunts metabolic promotes tumorigenesis that, intriguingly, coincides increases serum (BA) levels. Despite similar genetics, found BA concentrations males, whereas excreted more BAs. Decreasing enterohepatic recirculation using cholestyramine, an FDA-approved resin, dramatically reduced burden male mice. Overall, reveal sex-specific metabolism leading lower circulating concentration protects from developing cancer. Thus, targeting excretion may be promising strategy against HCC.