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

Abstract

ObjectivePeroxisome 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.MethodsWe investigated the biochemical interaction between PGC-1α and XBP1s and examined the role of their interaction in glucose homeostasis using animal models.ResultsWe 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.ConclusionsOur 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.

Transcriptional Coactivator PGC-1α Binding to Newly Synthesized RNA via CBP80: A Nexus for Co- and Posttranscriptional Gene Regulation

“…Although Mediator has been shown to play many roles in transcription (Allen and Taatjes 2015), the mechanism by which PGC-1α binding to MED1 promotes gene transcription is unclear. In addition to its transcriptional coactivator function, PGC-1α acts as a transcriptional repressor, as illustrated by its binding to and inhibition of the transcription factor XBP1s (Lee et al 2018), and also as an alternative splicing factor (Monsalve et al 2000;Martínez-Redondo et al 2016).…”

FOXO1 inhibition prevents renal ischemia–reperfusion injury via cAMP‐response element binding protein/PPAR‐γ coactivator‐1α‐mediated mitochondrial biogenesis

“…But up‐regulated FOXO1 was accompanied by a reduction of PGC‐1α, while PGC‐1α overexpression suppressed the activation of FOXO1 and FOXO3 in muscle (Kang & Ji, ). Hepatic PGC‐1α facilitated gluconeogenesis through multiple pathways served as a co‐activator for FOXO1 (Lee et al, ). Here, our results showed that elevated FOXO1 reduced PGC‐1α mRNA and protein levels, while FOXO1 inhibition increased transcription of PGC‐1α both in vivo and in vitro.…”

The orphan nuclear receptor SHP regulates ER stress response by inhibiting XBP1s degradation

“…The XBP1s protein is known to be unstable (Calfon et al 2002); however, the underlying mechanism remains poorly understood. A recent study suggested that PGC1α represses XBP1s protein level in the liver by promoting its ubiquitination and degradation (Lee et al 2018). Interestingly, this study mapped amino acid residues 227-252 of XBP1s as required for its interaction with PGC1α (Lee et al 2018), distinct from residues 301-371, which are required to interact with SHP.…”

“…A recent study suggested that PGC1α represses XBP1s protein level in the liver by promoting its ubiquitination and degradation (Lee et al 2018). Interestingly, this study mapped amino acid residues 227-252 of XBP1s as required for its interaction with PGC1α (Lee et al 2018), distinct from residues 301-371, which are required to interact with SHP. Very recently, another study showed that XBP1s ubiquitination and protein stability in natural killer cells are modulated in response to interleukin-15 signaling (Wang et al 2019).…”