PGC-1α Functions As A Co-Suppressor Of XBP1s To Regulate Glucose Metabolism Jaemin Lee1,2,*, Mario Andrés Salazar Hernández2, Thomas Auen2, Patrick Mucka2, Justin Lee2 and Umut Ozcan2,* 1Department of New Biology, Daegu-Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Korea 2Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA. *Corresponding Author
Peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) promotes hepatic gluconeogenesis by activating HNF4α and FoxO1. PGC-1α expression in the liver is highly elevated in obese and diabetic conditions, leading to increased hepatic glucose production. Since its discovery, PGC-1α has been acknowledged solely as a direct co-activator for the transcriptional factors. Here, we show that PGC-1α physically interacts with the spliced form of X-box binding protein 1 (XBP1s), which plays an anti-gluconeogenic role in the liver by suppressing FoxO1 activity. The physical interaction between PGC-1α and XBP1s leads to suppression of XBP1s activity rather than its activation. Upregulating PGC-1α expression in the liver of lean mice lessens XBP1s protein levels and reducing PGC-1α levels in obese and diabetic mouse liver restores XBP1s protein induction. Taken together, our findings reveal a novel function of PGC-1α as a suppressor of XBP1s, suggesting that hepatic PGC-1α promotes gluconeogenesis through multiple pathways as a co-activator for HNF4α and FoxO1 and also as a suppressor for anti-gluconeogenic transcription factor XBP1s.
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