Format

Send to

Choose Destination
Mol Metab. 2018 Jan;7:119-131. doi: 10.1016/j.molmet.2017.10.010. Epub 2017 Oct 28.

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

Author information

1
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Current address: Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, 42988, Republic of Korea. Electronic address: jaeminlee@dgist.ac.kr.
2
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
3
Division of Endocrinology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: umut.ozcan@childrens.harvard.edu.

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.

KEYWORDS:

ER stress; Glucose homeostasis; Insulin resistance; PGC-1α; UPR; XBP1s

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center