PDF(Pubmed)
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.
摘要：
代谢（功能障碍）相关的脂肪性肝炎（MASH）是代谢（功能障碍）相关的脂肪肝（MAFLD）缺乏批准的临床药物的晚期阶段。腺苷A1受体（A1R），属于G蛋白偶联受体（GPCRs）超家族，主要分布在中枢神经系统和主要外周器官中，具有广泛的生理功能；然而，肝A1R在MAFLD中的确切作用尚不清楚.这里,我们报道,A1R的肝脏特异性耗竭加重,而过表达减弱小鼠饮食诱导的代谢相关脂肪肝(MAFL)/MASH.机械上,肝A1R的激活促进甾醇调节元件结合蛋白（SREBP）裂解激活蛋白（SCAP）与螯合体1（SQSTM1）的竞争性结合，而不是导致溶酶体中SCAP降解的蛋白激酶A（PKA）。减少的SCAP阻碍SREBP1c/2成熟并因此抑制从头脂肪生成和炎症。在MAFL/MASH和高脂饮食（HFD）喂养的小鼠中观察到较高的肝A1R表达，这被认为是生理适应性反应，因为A1R激动剂以A1R依赖性方式减弱MAFL/MASH。这些结果强调肝A1R是MAFL/MASH治疗的潜在靶标。
