Abstract

Sex differences in health and disease are evident in humans and many other animal species. However, the sex-related determinants are less understood, and the underlying mechanisms remain elusive. By analyzing the RNA-Seq data, we unexpectedly find that Slc39a11 is significantly associated with the non-alcoholic fatty liver disease pathway only in female mice, revealing a sex-specific role of Slc39a11 in liver metabolism. We then generate tissue-specific SLC39A11 knock-in and Slc39a11 knockout mice and find that female but not male SLC39A11- liver conditional overexpression (LKI) mice develop more severe cholestasis and liver injury compared to controls when fed a methionine/choline-deficient (MCD) diet. In contrast, female Slc39a11 -liver conditional knockout (LKO) mice exhibit attenuated liver injury under MCD feeding. Ovariectomy in female mice largely reversed these phenotypes. Interestingly, female SLC39A11 -intestine-specific overexpression (IKI) mice show alleviated liver damage, whereas female Slc39a11 -intestine-specific knockout (IKO) mice develop exacerbated liver injury under MCD feeding; these effects are not observed in male SLC39A11 -IKI or Slc39a11 -IKO mice. This study reveals that SLC39A11 regulates liver metabolism both intrinsically and via the gut-liver axis through an evolutionarily conserved, sexual dimorphism mechanism, partially involving estrogen signaling and manganese metabolism, suggesting SLC39A11 is a potential target for the diagnosis and treatment of hepatobiliary diseases.