METABOLISM. S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction.

Science
Authors
Keywords
Abstract

The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, if and how chronic inflammation regulates the unfolded protein response (UPR) and alters ER homeostasis in general, or in the context of chronic disease, remains unknown. Here, we show that, in the setting of obesity, inflammatory input through increased inducible nitric oxide synthase (iNOS) activity causes S-nitrosylation of a key UPR regulator, IRE1α, which leads to a progressive decline in hepatic IRE1α-mediated XBP1 splicing activity in both genetic (ob/ob) and dietary (high-fat diet-induced) models of obesity. Finally, in obese mice with liver-specific IRE1α deficiency, reconstitution of IRE1α expression with a nitrosylation-resistant variant restored IRE1α-mediated XBP1 splicing and improved glucose homeostasis in vivo. Taken together, these data describe a mechanism by which inflammatory pathways compromise UPR function through iNOS-mediated S-nitrosylation of IRE1α, which contributes to defective IRE1α activity, impaired ER function, and prolonged ER stress in obesity.

Year of Publication
2015
Journal
Science
Volume
349
Issue
6247
Pages
500-6
Date Published
2015 Jul 31
ISSN
1095-9203
URL
DOI
10.1126/science.aaa0079
PubMed ID
26228140
PubMed Central ID
PMC4573582
Links
Grant list
R01 DK052539 / DK / NIDDK NIH HHS / United States
T32 GM007367 / GM / NIGMS NIH HHS / United States
DK052539 / DK / NIDDK NIH HHS / United States