Indole-3-acetic acid improves the hepatic mitochondrial respiration defects by PGC1a up-regulation

• Published in: Cellular signalling 2022-11, Vol.99, p.110442-110442, Article 110442
• Main Authors: Zhang, Chen, Fu, Qingsong, Shao, Kai, Liu, Limin, Ma, Xiaotian, Zhang, Fengyi, Zhang, Xiaodong, Meng, Liying, Yan, ChuanZhu, Zhao, Xiaoyun
• Format: Article
• Language: English
• Subjects: Indole-3-acetic acid; Mitochondria; Non-alcoholic fatty liver disease; Oxidative phosphorylation; Peroxisome proliferator-activated receptor gamma coactivator 1-alpha
• ISSN: 0898-6568; 1873-3913
• DOI: 10.1016/j.cellsig.2022.110442

Recent evidences have linked indole-3-acetic acid (I3A), a gut microbiota-derived metabolite from dietary tryptophan, with the protection against non-alcoholic fatty liver disease (NAFLD). However, the values of I3A on mitochondrial homeostasis in NAFLD have yet to be analyzed. In this study, we verified that I3A alleviated dietary-induced metabolic impairments, particularly glucose dysmetabolism and liver steatosis. Importantly, we expanded the understanding of I3A further to enhance mitochondrial oxidative phosphorylation in the liver by RNA-seq. Consistently, I3A restored the deficiency of mitochondrial respiration complex (MRC) capacity in palmitic acid (PA)-induced HepG2 without initiating oxidative stress in vitro. These changes were dependent on peroxisome proliferator-activated receptor γ coactivator 1 (PGC1)-a, a key regulator of mitochondrial biogenesis. Silencing of PGC1a by siRNA and pharmacologic inhibitor SR-18292, blocked the restoration of I3A on mitochondrial oxidative phosphorylation. In addition, pre-treatment of I3A guarded against the deficiency of MRC capacity. In conclusion, our findings uncovered that I3A increased hepatic PGC1a expression, contributing to mitochondrial respiration improvement in NAFLD. •I3A alleviates the mitochondrial respiration defects in HFD-fed mice liver and PA-induced HepG2 cells.•I3A recovers hepatic mitochondrial respiration defects through the PGC1-a pathway in vitro.•I3A may be a potential therapeutic approach for NAFLD.