ER stress promotes mitochondrial calcium overload and activates the ROS/NLRP3 axis to mediate fatty liver ischemic injury

作者：Fei Li, Zhu Guan, Yiyun Gao, Yan Bai, Xinyu Zhan, Xingyue Ji, Jian Xu, Haoming Zhou, Zhuqing Rao · 发表于：Hepatology Communications · 年份：2024 · DOI：10.1097/hc9.0000000000000399 · 被引用次数：54 · 研究领域：Organ Transplantation Techniques and Outcomes、Liver Disease and Transplantation、Liver physiology and pathology

BACKGROUND: Fatty livers are widely accepted as marginal donors for liver transplantation but are more susceptible to liver ischemia and reperfusion (IR) injury. Increased macrophage-related inflammation plays an important role in the aggravation of fatty liver IR injury. Here, we investigate the precise mechanism by which endoplasmic reticulum (ER) stress activates macrophage NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signaling by regulating mitochondrial calcium overload in fatty liver IR. METHODS: Control- and high-fat diet-fed mice were subjected to a partial liver IR model. The ER stress, mitochondrial calcium levels, and NLRP3 signaling pathway in macrophages were analyzed. RESULTS: Liver steatosis exacerbated liver inflammation and IR injury and enhanced NLRP3 activation in macrophages. Myeloid NLRP3 deficiency attenuated intrahepatic inflammation and fatty liver injury following IR. Mechanistically, increased ER stress and mitochondrial calcium overload were observed in macrophages obtained from mouse fatty livers after IR. Suppression of ER stress by tauroursodeoxycholic acid effectively downregulated mitochondrial calcium accumulation and suppressed NLRP3 activation in macrophages, leading to decreased inflammatory IR injury in fatty livers. Moreover, Xestospongin-C-mediated inhibition of mitochondrial calcium influx decreased reactive oxygen species (ROS) expression in macrophages after IR. Scavenging of mitochondrial ROS by mito-TEMPO su...