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

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.