2. Academic Validation
  3. 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: [email protected].
  • 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: [email protected].
  • 11 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
  • 12 School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
PMID: 38508143 DOI: 10.1016/j.xcrm.2024.101477
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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