Background: Although both are involved in metabolic homeostasis, the interconnection between ER stress and FGF21 remains incompletely understood. Results: Directly up-regulated by the IRE1␣-XBP1 pathway, FGF21 could alleviate ER stress-induced liver steatosis. Conclusion: FGF21 acts as a metabolic effector of the UPR program, exerting feedback effects upon lipid metabolism. Significance: These findings reveal a regulatory mechanism linking FGF21 actions to metabolic ER stress.

Although the mammalian IRE1a-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1a signalling in vivo remains poorly understood. Here we show that hepatic IRE1a functions as a nutrient sensor that regulates the metabolic adaptation to fasting. We find that prolonged deprivation of food or consumption of a ketogenic diet activates the IRE1a-XBP1 pathway in mouse livers. Hepatocyte-specific abrogation of Ire1a results in impairment of fatty acid b-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1a null mice. XBP1s directly binds to and activates the promoter of PPARa, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1a promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial b-oxidation and ketogenesis through the XBP1s-PPARa axis.