Constitutive Hepatic mTORC1 Activation Aggravates Alcohol-Induced Liver Injury via Endoplasmic Reticulum Stress–Mediated Ferroptosis

IF 4.7 2区 医学 Q1 PATHOLOGY
Lin Xu , Yuanyuan Zhao , Yang Yang , Enbo Qi , Boao Liu , Peili Zhuang , Shiyi Song , Tingmin Chang , Zhiguo Chen , Xiaohong Kang , Xiwen Xiong
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Abstract

Alcohol-related liver disease (ALD), a consequence of excessive alcohol use, manifests across a broad spectrum of liver damage, ranging from steatosis to cirrhosis. DEPDC5 (DEP domain–containing protein 5) is a component of the GATOR1 (gap activity towards rags 1) complex, which functions as a repressor of the amino acid–sensing branch of the mammalian target of rapamycin complex 1 (mTORC1) pathway. In this study, hepatocyte-specific Depdc5 knockout mice (Depdc5△Hep) were generated. Aberrant activation of mTORC1 caused by Depdc5 deletion led to exacerbated endoplasmic reticulum (ER) stress and hepatocyte ferroptosis in the livers of ethanol-fed mice. Torin-1, an ATP-competitive mTOR inhibitor, suppressed the mTORC1 activity and reversed the effects of Depdc5 deletion on ER stress and ferroptosis in ethanol-fed mouse livers. Furthermore, pharmacologic relief of ER stress using tauroursodeoxycholic acid or inhibition of ferroptosis with liproxstatin-1 both alleviated the liver abnormalities induced by Depdc5 ablation in ethanol-fed mice. In addition, ER stress was shown to function as an upstream signal of ferroptosis in the progression of ALD. These findings provide novel in vivo evidence that sustained mTORC1 activation leads to alcoholic liver injury by inducing ER stress and ferroptosis, suggesting that targeting these pathways may represent a potential therapeutic strategy for ALD.
组成性肝mTORC1激活通过内质网应激介导的铁下沉加重酒精诱导的肝损伤。
酒精相关性肝病(ALD)是过度饮酒的后果,表现为广泛的肝损害,从脂肪变性到肝硬化。DEPDC5 (DEP结构域含蛋白5)是GATOR1 (gap activity towards rags 1)复合物的一个组成部分,GATOR1是哺乳动物雷帕霉素靶蛋白复合物1 (mTORC1)途径氨基酸敏感分支的抑制因子。本研究生成肝细胞特异性Depdc5敲除小鼠(Depdc5△Hep),发现由Depdc5缺失引起的mTORC1异常激活导致乙醇喂养小鼠肝脏内质网(ER)应激加剧和肝细胞铁凋亡。Torin-1是一种atp竞争性mTOR抑制剂,可抑制mTORC1活性,逆转Depdc5缺失对乙醇喂养小鼠肝脏内质网应激和铁下垂的影响。此外,牛磺酸去氧胆酸对内质网应激的药理学缓解或利普司他汀-1对铁下垂的抑制均可减轻乙醇喂养小鼠因depc5消融引起的肝脏异常。此外,研究发现内质网应激在ALD的进展中作为铁下垂的上游信号起作用。这些发现提供了新的体内证据,表明持续的mTORC1激活通过诱导内质网应激和铁上睑下沉导致酒精性肝损伤,表明靶向这些途径可能代表了ALD的潜在治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
11.40
自引率
0.00%
发文量
178
审稿时长
30 days
期刊介绍: The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.
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