Uncovering Sex‐specific Roles of Farnesoid X Receptor in Heme Metabolism and Liver Proliferation

Abstract

Nuclear receptor, Farnesoid X Receptor (FXR), regulates bile acid homeostasis and has been shown to promote liver regenerative response. Serendipitously, we uncovered a distinct role for FXR in mediating liver injury response in female compared to male mice challenged with 3,5‐diethoxycarboncyl‐1,4‐dihydrocollidine (DDC, a heme biosynthesis disruptor). As expected, the DDC diet led to liver injury as measured by elevated serum ALT and AST levels in both control and FxrKO mice. Furthermore, accumulation of bile plugs and ductular reaction was visible in the WT mice, whereas both of these histological hallmarks were dramatically reduced in FxrKO mice. Despite similar histology, the proliferative response in the hepatocytes were different between both the sexes of FxrKO animals. Loss of Fxr resulted in increased hepatocyte size and low‐grade Ki‐67 positive hepatocyte nuclei even under basal conditions. But upon DDC challenge, FxrKO female livers displayed a dramatic induction of Ki‐67 positive staining even though no bile duct injury was visible. This finding correlated well with increased expression of cyclins. On the contrary, Ki‐67 staining was comparable between male FxrKO livers fed either chow or DDC diet, which matches with lower injury. We are actively investigating the crosstalk of estrogen signaling with FXR in controlling liver proliferation. At the molecular level, genes regulating the cell cycle (Ccnd1, Ccna, Ccnb1) were induced upon injury in the male livers in an Fxr‐dependent manner, whereas this response was not observed in female livers. Expression of Cyp2b10 and Cyp3a11, which are known detoxification genes, were induced with DDC treatment. To test if the absence of bile plugs in FxrKO mice is secondary to reduced heme synthesis in these livers, we examined the heme biosynthetic pathway. We mined previously published data and found strong Fxr occupancy and binding to 6 out of the 8 genes involved in the heme synthesis pathway including Alas1, which is the rate‐limiting step in heme biosynthesis. In summary, FXR may regulate heme metabolism and modulate hepatocyte proliferation in a sex‐specific manner.Support or Funding InformationResearch Scholar Grant TBE 132315