I3A Improves the Hepatic Mitochondrial Respiration Defects in NAFLD Disease Model. I3A Improves the Hepatic Mitochondrial Respiration Defects in NAFLD Disease Model

Recent evidences have linked indole-3-acetic acid (I3A), a gut microbiota-derived metabolite from dietary tryptophan, with the resistance to liver diseases. However, data supporting I3A-mediated protection against nonalcoholic fatty liver disease (NAFLD) remain incomprehensive. In this study, we verified that I3A definitely alleviates dietary-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis. Importantly, we expand the understanding of I3A further to enhancing mitochondrial respiration complex (MRC) capacity by RNA-seq. We found that I3A restored the deficiency of MRC capacity in palmitic acid (PA)-induced HepG2 in vitro. These changes were associated with complex I and III expression and their activities. In addition, pre-treatment of I3A guard against the deficiency of not only the MRC capacity but also ATP production due to the advanced protection effect on the expression and activity of complex V. In conclusion, our findings uncover that I3A increased expression and activity of hepatic oxidative phosphorylation subunits, contributing to mitochondrial respiration improvement in NAFLD mice. Overall design: Liver mRNA profiles of HFD and HFD+I3A mice

现有研究证据表明，吲哚-3-乙酸（I3A）——一种由膳食色氨酸经肠道菌群代谢产生的代谢物——与肝脏疾病的抗性存在关联。然而，支持I3A介导的非酒精性脂肪肝病（NAFLD）保护作用的相关数据仍不够全面。本研究证实，I3A可显著缓解膳食诱导的代谢异常，尤其是糖代谢紊乱与肝脏脂肪变性。值得关注的是，我们通过RNA测序（RNA-seq）进一步拓展了对I3A作用机制的认知，发现其可提升线粒体呼吸复合物（MRC）的功能容量。体外实验显示，I3A可恢复棕榈酸（PA）诱导的HepG2细胞线粒体呼吸复合物功能缺陷，该效应与复合物I、III的表达水平及活性密切相关。此外，I3A预处理可同时抵御线粒体呼吸复合物功能缺陷与三磷酸腺苷（ATP）生成不足，这源于其对复合物V表达与活性的优异保护作用。综上，本研究揭示I3A可上调肝脏氧化磷酸化亚基的表达并增强其活性，从而改善非酒精性脂肪肝病小鼠的线粒体呼吸功能。实验设计概述：高脂饮食（High Fat Diet, HFD）小鼠与高脂饮食联合I3A干预小鼠的肝脏mRNA表达谱分析