Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

Abstract

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.

XBP1s Is an Anti-lipogenic Protein

“…We (14 -16) and others (42,43) have previously identified XBP1s as a crucial regulator of glucose homeostasis in obesity. XBP1s action is severely impaired in mouse models of obesity (13), and this relative "XBP1s deficiency" contributes to the development of sustained ER stress, pathological activation of UPR signaling (13), and, ultimately, to disturbed glucose homeostasis.…”

Fibroblast Growth Factor 21 Is Regulated by the IRE1α-XBP1 Branch of the Unfolded Protein Response and Counteracts Endoplasmic Reticulum Stress-induced Hepatic Steatosis

“…For the tunicamycin-induced ER stress animal model, mice at 12 weeks of age were injected intraperitoneally with DMSO or tunicamycin (Sigma) at a dose of 1 mg/kg body weight and sacrificed after 24 h of treatment. Mice with liver-specific knock-out of IRE1␣ (LKO) were bred as described previously (44). For examination of the effect of FGF21 on ER stress, mice at 12 weeks were treated with DMSO or tunicamycin (1 mg/kg body weight), and starting at 6 h before tunicamycin injection, recombinant mouse FGF21 (PeproTech) was administered intraperitoneally at 1 mg/kg body weight for a total of five times every 6 h. Mice were sacrificed at 24 h after tunicamycin treatment.…”

“…This implies that FGF21 is also likely to exert cytoprotective functions in other tissues such as the kidney, an organ that can be very sensitive to ER stress. (42,43), we tested whether FGF21 is a common downstream target of multiple UPR pathways using liver-specific IRE1␣ knock-out (LKO) mice that we created (44). Interestingly, when compared with flox/flox control mice, tunicamycin-treated LKO mice had lower serum FGF21 levels (Fig.…”

“…We previously showed that the IRE1␣ pathway is activated in the liver during fasting or starvation (44,47). Hepatic IRE1␣ can sense nutrient deprivation and regulate the adaptive shift of fuel utilization through XBP1s-directed regulation of PPAR␣.…”

Physiological/pathological ramifications of transcription factors in the unfolded protein response

“…Hepatic overexpression of XBP1s suppresses gluconeogenesis through its interaction with FoxO1 to promote its degradation through the 26S proteasome system (Zhou et al 2011). On the other hand, upon prolonged fasting, XBP1s directly induces expression of PPARα, the master regulator of the starvation response, leading to fatty acid β-oxidation and ketogenesis in the liver (Shao et al 2014). XBP1s was reported to directly induce transcription of lipogenic genes in the liver, including Dgat2, Scd1, and Acc2 ).…”