Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation
Weize Zhu, Ying Hong, Zhaowei Tong, Xiaofang He, Yan Li, Hao Wang, Xinxin Gao, Pengtao Song, Xianshan Zhang, Xiaochang Wu, Zhenhua Tan, Wenjin Huang, Zekun Liu, Yiyang Bao, Junli Ma, Ningning Zheng, Cen Xie, Xisong Ke, Wen Zhou, Wei Jia, Mingxiao Li, Jing Zhong, Lili Sheng, Houkai Li
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 (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.