Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is an important phase in the progression of metabolic dysfunction-associated steatotic liver disease to end-stage liver diseases, posing an increasing threat to public health worldwide with limited treatment options. Here we show that GPR110 is a liver-selective G-protein-coupled receptor closely associated with MASH in a sex-specific manner. Hepatocyte-specific Gpr110 knockout protects against MASH in female, but not male mice. The GPR110 variant rs937057 T > C is associated with a higher prevalence of metabolic dysfunction-associated steatotic liver disease in women. The improved liver phenotypes in female mice are abrogated by knocking down the expression of hepatic oestrogen receptor alpha ( Esr1 ). Mechanistically, GPR110 couples to Gα s and activates protein kinase A, thereby inducing phosphorylation of NFAT2, which inhibits its nuclear translocation and transcriptional activity, leading to suppressed Esr1 transcription in hepatocytes. Taken together, these results demonstrate a sex-specific role of GPR110 in MASH by regulating hepatic oestrogen sensitivity, suggesting inhibition of GPR110 as a potential sex-specific therapy for MASH.