%0 Journal Article
%T Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation.
%A Zhu W
%A Hong Y
%A Tong Z
%A He X
%A Li Y
%A Wang H
%A Gao X
%A Song P
%A Zhang X
%A Wu X
%A Tan Z
%A Huang W
%A Liu Z
%A Bao Y
%A Ma J
%A Zheng N
%A Xie C
%A Ke X
%A Zhou W
%A Jia W
%A Li M
%A Zhong J
%A Sheng L
%A Li H
%J Cell Rep Med
%V 5
%N 3
%D 2024 Mar 19
%M 38508143
%F 16.988
%R 10.1016/j.xcrm.2024.101477
%X 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.