安徽医科大学黄艳等研究人员合作发现，酸感受离子通道1a通过调节内质网自噬促进小鼠酒精相关性肝病的发展。这一研究成果于2024年11月26日在线发表在国际学术期刊《中国药理学报》上。

研究人员探讨了内质网自噬（ER-phagy）在酒精相关性肝病（ALD）中的作用，以及酸感受离子通道1a（ASIC1a）在内质网应激介导的内质网自噬中的作用。研究人员通过高饮酒法建立了ALD小鼠模型，并使用酒精处理的AML12细胞系作为体外模型。

研究表明，在体内和体外模型中，ASIC1a的表达显著增加，且内质网自噬被激活。在酒精处理的AML12细胞中，研究人员发现用PcTx-1阻断ASIC1a或敲低ASIC1a，可以减少酒精引起的细胞内Ca²⁺积累和内质网应激。

此外，使用4-PBA抑制内质网应激可以减少内质网自噬的水平。进一步地，敲低具有序列相似性134成员B（FAM134B）的内质网自噬受体家族，缓解了酒精引发的肝细胞损伤和凋亡。

综上所述，该研究表明，酒精通过增加ASIC1a表达和ASIC1a介导的Ca²⁺流入激活内质网应激诱导的内质网自噬以及肝损伤，为ALD的治疗提供了新的策略。

据介绍，ALD是一种由长期或过量饮酒引起的肝细胞功能障碍性疾病，可能导致广泛的肝细胞坏死，甚至肝衰竭。目前，ALD的发病机制以及抗ALD的机制尚未完全阐明。

附：英文原文

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

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

Issue&Volume: 2024-11-26

Abstract: 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 Ca2+ 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 Ca2+ influx, providing a novel strategy for the treatment of ALD.

DOI: 10.1038/s41401-024-01423-4

Source: https://www.nature.com/articles/s41401-024-01423-4