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<p>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 <i>Gpr110</i> knockout protects against MASH in female, but not male mice. The <i>GPR110</i> variant <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs937057">rs937057</a> T &gt; 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 (<i>Esr1</i>). Mechanistically, GPR110 couples to Gα<sub>s</sub> and activates protein kinase A, thereby inducing phosphorylation of NFAT2, which inhibits its nuclear translocation and transcriptional activity, leading to suppressed <i>Esr1</i> 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.</p>

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Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling

  • 期刊论文

  • 发表日期：

    2026年1月5日

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  • Fang Yang,
  • Wei Wang,
  • Feng Qiu,
  • Rui Qing,
  • Qingying Gao,
  • Xingqun Yan,
  • Donghai Wu,
  • Hannah Xiaoyan Hui,
  • Rui Dang,
  • Guozhi Jiang,
  • Liyuan Han,
  • Chunhao Long,
  • Shuang Hua,
  • Yixuan Zhang,
  • Siwei Ji,
  • Lu Xu,
  • Chen Zhou,
  • Daiqiang Xu,
  • Alessandro Cherubini,
  • Luca Valenti,
  • Ping Gu,
  • Shufei Zang,
  • Weimin Jiang,
  • Zhe Huang

摘要

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 Gαs 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.