1. Academic Validation
  2. Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation

Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation

  • Cell Rep Med. 2024 Mar 19;5(3):101477. doi: 10.1016/j.xcrm.2024.101477.
Weize Zhu 1 Ying Hong 1 Zhaowei Tong 2 Xiaofang He 1 Yan Li 1 Hao Wang 1 Xinxin Gao 1 Pengtao Song 3 Xianshan Zhang 2 Xiaochang Wu 4 Zhenhua Tan 4 Wenjin Huang 1 Zekun Liu 1 Yiyang Bao 1 Junli Ma 1 Ningning Zheng 1 Cen Xie 5 Xisong Ke 6 Wen Zhou 7 Wei Jia 8 Mingxiao Li 9 Jing Zhong 10 Lili Sheng 11 Houkai Li 12
Affiliations

Affiliations

  • 1 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China.
  • 3 Department of Pathology, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China.
  • 4 Department of Hepatobiliary Surgery, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China.
  • 5 Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 6 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 7 Key Laboratory of Veterinary Chemical Drugs and Pharmaceutics, Ministry of Agriculture and Rural, Affairs, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai 200241, China.
  • 8 School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China.
  • 9 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: mingxiaoli0928@126.com.
  • 10 Huzhou Key Laboratory of Precision Medicine Research and Translation for Infectious Diseases, Huzhou Central Hospital, Affiliated Central Hospital Huzhou University, Huzhou 313000, China. Electronic address: Zhongjing1003@126.com.
  • 11 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: llsheng@shutcm.edu.cn.
  • 12 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: hk_li@shutcm.edu.cn.
Abstract

Metabolic (dysfunction)-associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction)-associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A1R), belonging to the G-protein-coupled receptors (GPCRs) superfamily, is mainly distributed in the central nervous system and major peripheral organs with wide-ranging physiological functions; however, the exact role of hepatic A1R in MAFLD remains unclear. Here, we report that liver-specific depletion of A1R aggravates while overexpression attenuates diet-induced metabolic-associated fatty liver (MAFL)/MASH in mice. Mechanistically, activation of hepatic A1R promotes the competitive binding of sterol-regulatory element binding protein (SREBP) cleavage-activating protein (SCAP) to sequestosome 1 (SQSTM1), rather than protein kinase A (PKA) leading to SCAP degradation in lysosomes. Reduced SCAP hinders SREBP1c/2 maturation and thus suppresses de novo lipogenesis and inflammation. Higher hepatic A1R expression is observed in patients with MAFL/MASH and high-fat diet (HFD)-fed mice, which is supposed to be a physiologically adaptive response because A1R agonists attenuate MAFL/MASH in an A1R-dependent manner. These results highlight that hepatic A1R is a potential target for MAFL/MASH therapy.

Keywords

MASH; SCAP-SREBPs pathway; adenosine A1 receptor; de novo lipogenesis; inflammation.

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