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

文献类型： 外文期刊

第一作者： Zhu, Weize

作者： Zhu, Weize;Hong, Ying;He, Xiaofang;Li, Yan;Wang, Hao;Gao, Xinxin;Huang, Wenjin;Liu, Zekun;Bao, Yiyang;Ma, Junli;Zheng, Ningning;Li, Mingxiao;Sheng, Lili;Li, Houkai;Tong, Zhaowei;Zhang, Xianshan;Zhong, Jing;Song, Pengtao;Wu, Xiaochang;Tan, Zhenhua;Xie, Cen;Ke, Xisong;Zhou, Wen;Jia, Wei

作者机构：

期刊名称：CELL REPORTS MEDICINE （ 影响因子：14.3； 五年影响因子：14.3 ）

ISSN： 2666-3791

年卷期： 2024 年 5 卷 3 期

页码：

收录情况： SCI

摘要： Metabolic (dysfunction) -associated steatohepatitis (MASH) is the advanced stage of metabolic (dysfunction) -associated fatty liver disease (MAFLD) lacking approved clinical drugs. Adenosine A1 receptor (A 1 R), 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 A 1 R in MAFLD remains unclear. Here, we report that liver -specific depletion of A 1 R aggravates while overexpression attenuates diet -induced metabolic -associated fatty liver (MAFL)/ MASH in mice. Mechanistically, activation of hepatic A 1 R 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 A 1 R 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 A 1 R agonists attenuate MAFL/MASH in an A 1 R-dependent manner. These results highlight that hepatic A 1 R is a potential target for MAFL/ MASH therapy.

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