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PGC-1α functions as a co-suppressor of XBP1s to regulate glucose metabolism

Title
PGC-1α functions as a co-suppressor of XBP1s to regulate glucose metabolism
Authors
Lee, Jae MinSalazar Hernández, Mario AndrésAuen, ThomasMucka, PatrickLee, JustinOzcan, Umut
DGIST Authors
Lee, Jae Min
Issue Date
2018-01
Citation
Molecular Metabolism, 7, 119-131
Type
Article
Article Type
Article
ISSN
2212-8778
Abstract
Objective 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. 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-1α and XBP1s in regulating FoxO1 activity and gluconeogenesis led us to investigate the probable interaction between PGC-1α and XBP1s and its role in glucose metabolism. Methods We investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models. Results We show that PGC-1α interacts with 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. Conclusions Our findings reveal a novel function of PGC-1α as a suppressor of XBP1s function, 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. © 2017 The Authors
URI
http://hdl.handle.net/20.500.11750/5603
DOI
10.1016/j.molmet.2017.10.010
Publisher
Elsevier GmbH
Related Researcher
  • Author Lee, Jae Min Lab of Aging, Metabolism and Physiology
  • Research Interests
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Collection:
New BiologyLab of Aging, Metabolism and Physiology1. Journal Articles


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