2. Academic Validation
  3. Hepatic GPR110 contributes to sex disparity in the development of MASH through oestrogen receptor α-dependent signalling

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

  • Nat Metab. 2026 Jan;8(1):116-138. doi: 10.1038/s42255-025-01436-1.
Fang Yang # 1,  Wei Wang # 2,  Feng Qiu 1,  Rui Qing 1,  Qingying Gao 1,  Xingqun Yan 1,  Donghai Wu 3,  Hannah Xiaoyan Hui 4,  Rui Dang 5,  Guozhi Jiang 5,  Liyuan Han 6 7,  Chunhao Long 1,  Shuang Hua 8,  Yixuan Zhang 1,  Siwei Ji 1,  Lu Xu 9,  Chen Zhou 10,  Daiqiang Xu 2,  Alessandro Cherubini 11,  Luca Valenti 11 12,  Ping Gu 13 14,  Shufei Zang 15,  Weimin Jiang 16,  Zhe Huang 17 18
Affiliations

Affiliations

  • 1 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Department of Endocrinology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 3 Guangzhou Institute of Biomedical Health, Chinese Academy of Sciences, Guangzhou, China.
  • 4 School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
  • 5 School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, China.
  • 6 Department of Clinical Epidemiology, Ningbo, China.
  • 7 Center for Cardiovascular and Cerebrovascular Epidemiology and Translational Medicine, Guoke Ningbo Life Science and Health Industry Research Institute, University of Chinese Academy of Sciences, Ningbo, China.
  • 8 Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
  • 9 School of Life Sciences, Westlake University, Hangzhou, China.
  • 10 Department of Ultrasound, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 11 Precision Medicine-Biological Resource Center and Department of Transfusion Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • 12 Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
  • 13 Department of Endocrinology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China. [email protected].
  • 14 Department of Endocrinology, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Nanjing, China. [email protected].
  • 15 Department of Endocrinology, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China. [email protected].
  • 16 Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China. [email protected].
  • 17 School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China. [email protected].
  • 18 Department of Cardiology, Shanghai Pudong New Area People's Hospital, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41491303 DOI: 10.1038/s42255-025-01436-1
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 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.

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