| First Author | Shao M | Year | 2014 |
| Journal | Nat Commun | Volume | 5 |
| Pages | 3528 | PubMed ID | 24670948 |
| Mgi Jnum | J:210463 | Mgi Id | MGI:5571223 |
| Doi | 10.1038/ncomms4528 | Citation | Shao M, et al. (2014) Hepatic IRE1alpha regulates fasting-induced metabolic adaptive programs through the XBP1s-PPARalpha axis signalling. Nat Commun 5:3528 |
| abstractText | Although the mammalian IRE1alpha-XBP1 branch of the cellular unfolded protein response has been implicated in glucose and lipid metabolism, the exact metabolic role of IRE1alpha signalling in vivo remains poorly understood. Here we show that hepatic IRE1alpha 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 IRE1alpha-XBP1 pathway in mouse livers. Hepatocyte-specific abrogation of Ire1alpha results in impairment of fatty acid beta-oxidation and ketogenesis in the liver under chronic fasting or ketogenic conditions, leading to hepatosteatosis; liver-specific restoration of XBP1s reverses the defects in IRE1alpha null mice. XBP1s directly binds to and activates the promoter of PPARalpha, the master regulator of starvation responses. Hence, our results demonstrate that hepatic IRE1alpha promotes the adaptive shift of fuel utilization during starvation by stimulating mitochondrial beta-oxidation and ketogenesis through the XBP1s-PPARalpha axis. |
