{Reference Type}: Journal Article
{Title}: Activation of hepatic adenosine A1 receptor ameliorates MASH via inhibiting SREBPs maturation.
{Author}: Zhu W;Hong Y;Tong Z;He X;Li Y;Wang H;Gao X;Song P;Zhang X;Wu X;Tan Z;Huang W;Liu Z;Bao Y;Ma J;Zheng N;Xie C;Ke X;Zhou W;Jia W;Li M;Zhong J;Sheng L;Li H;
{Journal}: Cell Rep Med
{Volume}: 5
{Issue}: 3
{Year}: 2024 Mar 19
{Factor}: 16.988
{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.