Acid-sensing ion channel 1a promotes alcohol-associated liver disease in mice via regulating endoplasmic reticulum autophagy  

作　　者：Yue-qin Zhu Li-li Wang Zi-hao Li Shi-shun Qian Zhou Xu Jin Zhang Yong-hu Song Xue-sheng Pan Na Du Amira Abou-Elnour Lynn Jia Tay Jing-rong Zhang Meng-xue Li Yu-xian Shen Yan Huang 

机构地区：[1]Department of Pharmacy,The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,University of Science and Technology of China,Hefei,230001,China [2]Office of Clinical Trial Institution,Anhui Provincial Cancer Hospital,Hefei,230031,China [3]Anhui Province Key Laboratory of Major Autoimmune Diseases,Anhui Institute of Innovative Drugs,School of Pharmacy,Anhui Medical University,Hefei,230032,China [4]The First Affiliated Hospital of Anhui Medical University,Hefei,230032,China [5]Department of Immunology,School of Basic Medical Sciences,Anhui Medical University,Hefei,230032,China [6]Department of Pharmacy,Shanghai Songjiang District Central Hospital,Shanghai,201600,China [7]Department of Pharmacology,School of Basic Medical Sciences,Anhui Medical University,Hefei,230032,China

出　　处：《Acta Pharmacologica Sinica》2025年第4期989-1001,共13页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(82370591);Key Project of the Joint Fund of the National Natural Science Foundation of China(U21A20345);the Fundamental Research Funds for the Central Universities(WK9110000197);the Anhui Province Higher Education Science Research Project(Natural Science)(2023AH040078);the Horizontal Project(H2023031);the 2021 Academic Funding Project for Top Talents in Higher Education Discipline(Major)(gxbjZD2021048);the 2023 Hefei Natural Science Foundation Project(2023018);the 2023 Anhui Medical University Research Level Improvement Plan Project(2023xkiT010);Pharmaceutical Peak Discipline Talent Fund Project“Research oriented Young Talents”(2023xkkq3);Anhui Province Excellent Research and Innovation Team Project(2024AH010013);the Anhui Medical University International Students Innovation Training Program Project(GJY202305;S202410366120);the 2023 New Era Education Provincial Quality Engineering Project Graduate Joint Training Demonstration Base[2023lhpysfjd023];the Early Contact Research Projects(2022-ZQKY-80;2023-YXYZQKY-40).

摘　　要：Alcohol-associated liver disease(ALD)is a hepatocyte dysfunction disease caused by chronic or excessive alcohol consumption,which can lead to extensive hepatocyte necrosis and even liver failure.Currently,the pathogenesis of ALD and the anti-ALD mechanisms have not been fully elucidated yet.In this study,we investigated the effects of endoplasmic reticulum autophagy(ER-phagy)in ALD and the role of acid-sensing ion channel 1a(ASIC1a)in ER stress-mediated ER-phagy.A mouse model of ALD was established using the Gao-Binge method and the AML12 cell line treated with alcohol was used as an in vitro model.We showed that ASIC1a expression was significantly increased and ER-phagy was activated in both the in vivo and in vitro models.In alcohol-treated AML12 cells,we showed that blockade of ASIC1a with PcTx-1 or knockdown of ASIC1a reduced alcohol-induced intracellular Ca^(2+)accumulation and ER stress.In addition,inhibition of ER stress with 4-PBA reduced the level of ER-phagy.Furthermore,knockdown of the ER-phagy receptor family with sequence similarity 134 member B(FAM134B)alleviated alcohol-triggered hepatocyte injury and apoptosis.In conclusion,this study demonstrates that alcohol activates ER stress-induced ER-phagy and liver injury by increasing ASIC1a expression and ASIC1a-mediated Ca^(2+)influx,providing a novel strategy for the treatment of ALD.

关 键 词：alcohol-associated liver disease ASIC1a Ca^(2+)influx ER-phagy ER stress apoptosis 

分 类 号：R575[医药卫生—消化系统]