| First Author | Lee J | Year | 2018 |
| Journal | Mol Metab | Volume | 7 |
| Pages | 119-131 | PubMed ID | 29129613 |
| Mgi Jnum | J:270979 | Mgi Id | MGI:6161997 |
| Doi | 10.1016/j.molmet.2017.10.010 | Citation | Lee J, et al. (2018) PGC-1alpha functions as a co-suppressor of XBP1s to regulate glucose metabolism. Mol Metab 7:119-131 |
| abstractText | OBJECTIVE: Peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator-1alpha (PGC-1alpha) promotes hepatic gluconeogenesis by activating HNF4alpha and FoxO1. PGC-1alpha expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. We previously showed that the spliced form of X-box binding protein 1 (XBP1s) suppresses FoxO1 activity and hepatic gluconeogenesis. The shared role of PGC-1alpha and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1alpha and XBP1s and its role in glucose metabolism. METHODS: We investigated the biochemical interaction between PGC-1alpha and XBP1s and examined the role of their interaction in glucose homeostasis using animal models. RESULTS: We show that PGC-1alpha interacts with XBP1s, which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1alpha and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1alpha expression in the liver of lean mice lessens XBP1s protein levels, and reducing PGC-1alpha levels in obese and diabetic mouse liver restores XBP1s protein induction. CONCLUSIONS: Our findings reveal a novel function of PGC-1alpha as a suppressor of XBP1s function, suggesting that hepatic PGC-1alpha promotes gluconeogenesis through multiple pathways as a co-activator for HNF4alpha and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s. |
