A conventional immune regulator mitochondrial antiviral signaling protein blocks hepatic steatosis by maintaining mitochondrial homeostasis
A conventional immune regulator mitochondrial antiviral signaling protein blocks hepatic steatosis by maintaining mitochondrial homeostasis
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DOI：
10.1002/hep.32126
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发表时间：
2021-12-12
期刊：
影响因子：
13.5
通讯作者：
Li, Hongliang
中科院分区：
文献类型：
--
作者：
Fu, Jiajun;Hu, Fengjiao;Li, Hongliang
背景和目的虽然NAFLD的患病率已急剧上升至全球成年人群的25%，但由于对潜在分子机制的不确定性，尚未批准用于该疾病的药物干预。众所周知，线粒体功能障碍是NAFLD发展的重要因素。线粒体抗病毒信号蛋白（MAVS）是宿主抵抗病毒感染的关键信号衔接子。然而，MAVS在NAFLD进展期间线粒体代谢中的作用在很大程度上仍然未知。方法和结果基于表达分析，我们确定了NAFLD进展过程中肝细胞中MAVS的显著下调。通过使用MAVS整体敲除和肝细胞特异性MAVS敲除小鼠，我们发现MAVS对饮食诱导的NAFLD具有保护作用。MAVS缺陷在NAFLD发病过程中引起广泛的线粒体功能障碍，其被证实为线粒体呼吸能力和膜电位受损。代谢组学数据也显示MAVS缺失后广泛的代谢紊乱。从机制上讲，MAVS与电压依赖性阴离子通道2（VDAC 2）的N-末端片段相互作用，这是MAVS影响线粒体功能和肝脂肪变性的能力所必需的。结论在肝细胞中，MAVS通过帮助调节健康的线粒体功能在保护NAFLD中起重要作用。这些发现提供了关于常规免疫调节剂的代谢重要性的见解，并支持靶向MAVS可能代表治疗NAFLD的途径的可能性。
Background and Aims Although the prevalence of NAFLD has risen dramatically to 25% of the adult population worldwide, there are as yet no approved pharmacological interventions for the disease because of uncertainty about the underlying molecular mechanisms. It is known that mitochondrial dysfunction is an important factor in the development of NAFLD. Mitochondrial antiviral signaling protein (MAVS) is a critical signaling adaptor for host defenses against viral infection. However, the role of MAVS in mitochondrial metabolism during NAFLD progression remains largely unknown. Approach and Results Based on expression analysis, we identified a marked down-regulation of MAVS in hepatocytes during NAFLD progression. By using MAVS global knockout and hepatocyte-specific MAVS knockout mice, we found that MAVS is protective against diet-induced NAFLD. MAVS deficiency induces extensive mitochondrial dysfunction during NAFLD pathogenesis, which was confirmed as impaired mitochondrial respiratory capacity and membrane potential. Metabolomics data also showed the extensive metabolic disorders after MAVS deletion. Mechanistically, MAVS interacts with the N-terminal stretch of voltage-dependent anion channel 2 (VDAC2), which is required for the ability of MAVS to influence mitochondrial function and hepatic steatosis. Conclusions In hepatocytes, MAVS plays an important role in protecting against NAFLD by helping to regulate healthy mitochondrial function. These findings provide insights regarding the metabolic importance of conventional immune regulators and support the possibility that targeting MAVS may represent an avenue for treating NAFLD.