Journal article
S -Nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy
Diabetes (New York, N.Y.), Vol.67(2), pp.193-207
02/2018
DOI: 10.2337/db17-0223
PMID: 29074597
Abstract
Obesity is associated with elevated intracellular nitric oxide (NO) production, which promotes nitrosative stress in metabolic tissues such as liver and skeletal muscle, contributing to insulin resistance. The onset of obesity-associated insulin resistance is due, in part, to the compromise of hepatic autophagy, a process that leads to lysosomal degradation of cellular components. However, it is not known how NO bioactivity might impact autophagy in obesity. Here, we establish that
-nitrosoglutathione reductase (GSNOR), a major protein denitrosylase, provides a key regulatory link between inflammation and autophagy, which is disrupted in obesity and diabetes. We demonstrate that obesity promotes
-nitrosylation of lysosomal proteins in the liver, thereby impairing lysosomal enzyme activities. Moreover, in mice and humans, obesity and diabetes are accompanied by decreases in GSNOR activity, engendering nitrosative stress. In mice with a GSNOR deletion, diet-induced obesity increases lysosomal nitrosative stress and impairs autophagy in the liver, leading to hepatic insulin resistance. Conversely, liver-specific overexpression of GSNOR in obese mice markedly enhances lysosomal function and autophagy and, remarkably, improves insulin action and glucose homeostasis. Furthermore, overexpression of
-nitrosylation-resistant variants of lysosomal enzymes enhances autophagy, and pharmacologically and genetically enhancing autophagy improves hepatic insulin sensitivity in GSNOR-deficient hepatocytes. Taken together, our data indicate that obesity-induced protein
-nitrosylation is a key mechanism compromising the hepatic autophagy, contributing to hepatic insulin resistance.
Details
- Title: Subtitle
- S -Nitrosoglutathione Reductase Dysfunction Contributes to Obesity-Associated Hepatic Insulin Resistance via Regulating Autophagy
- Creators
- Qingwen Qian - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, The Pappajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City, IAZeyuan Zhang - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, The Pappajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City, IAAllyson Orwig - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, The Pappajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City, IASonghai Chen - Department of Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IAWen-Xing Ding - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KSYanji Xu - Shaun and Lilly International, LLC, Collierville, TNRyan C Kunz - Thermo Fisher Scientific Center for Multiplexed Proteomics, Harvard Medical School, Boston, MANicholas R L Lind - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, The Pappajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City, IAJonathan S Stamler - Institute for Transformative Molecular Medicine and Department of Medicine, Case Western Reserve University and Harrington Discovery Institute, University Hospitals, Cleveland, OHLing Yang - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, The Pappajohn Biomedical Institute, Carver College of Medicine, University of Iowa, Iowa City, IA ling-yang@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.67(2), pp.193-207
- Publisher
- United States
- DOI
- 10.2337/db17-0223
- PMID
- 29074597
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Grant note
- DOI: 10.13039/100000968, name: American Heart Association, award: Scientist Development Grant 15SDG25510016
- Language
- English
- Date published
- 02/2018
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Iowa Neuroscience Institute; Fraternal Order of Eagles Diabetes Research Center; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984025362002771
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