Succinate is an important metabolite and a critical chemical
with
diverse applications in the food, pharmaceutical, and agriculture
industries. Recent studies have demonstrated several protective or
detrimental functions of succinate in diseases; however, the effect
of succinate on lipid metabolism is still unclear. Here, we identified
a role of succinate in nonobese nonalcoholic fatty liver disease (NAFLD).
Specifically, the level of succinate is increased in the livers and
serum of mice with hepatic steatosis. The administration of succinate
promotes triglyceride (TG) deposition and hepatic steatosis by suppressing
fatty acid oxidation (FAO) in nonobese NAFLD mouse models. RNA-Seq
revealed that succinate suppressed fibroblast growth factor 21 (FGF21)
expression. Then, the restoration of FGF21 was sufficient to alleviate
hepatic steatosis and FAO inhibition induced by succinate treatment in vitro and in vivo. Furthermore, the
inhibition of FGF21 expression and FAO mediated by succinate was dependent
on the AMPK/PPARα axis. This study provides evidence linking
succinate exposure to abnormal hepatic lipid metabolism and the progression
of nonobese NAFLD.