Exposure to Succinate\nLeads to Steatosis in Non-Obese\nNon-Alcoholic Fatty Liver Disease by Inhibiting AMPK/PPARα/FGF21-Dependent\nFatty Acid Oxidation

Succinate is an important metabolite and a critical chemical\nwith\ndiverse applications in the food, pharmaceutical, and agriculture\nindustries. Recent studies have demonstrated several protective or\ndetrimental functions of succinate in diseases; however, the effect\nof succinate on lipid metabolism is still unclear. Here, we identified\na role of succinate in nonobese nonalcoholic fatty liver disease (NAFLD).\nSpecifically, the level of succinate is increased in the livers and\nserum of mice with hepatic steatosis. The administration of succinate\npromotes triglyceride (TG) deposition and hepatic steatosis by suppressing\nfatty acid oxidation (FAO) in nonobese NAFLD mouse models. RNA-Seq\nrevealed that succinate suppressed fibroblast growth factor 21 (FGF21)\nexpression. Then, the restoration of FGF21 was sufficient to alleviate\nhepatic steatosis and FAO inhibition induced by succinate treatment <i>in vitro</i> and <i>in vivo</i>. Furthermore, the\ninhibition of FGF21 expression and FAO mediated by succinate was dependent\non the AMPK/PPARα axis. This study provides evidence linking\nsuccinate exposure to abnormal hepatic lipid metabolism and the progression\nof nonobese NAFLD.