Journal article
Hepatic Lysosomal iNOS Activity Impairs Autophagy in Obesity
Cellular and molecular gastroenterology and hepatology, Vol.8(1), pp.95-110
2019
DOI: 10.1016/j.jcmgh.2019.03.005
PMCID: PMC6522853
PMID: 30926581
Abstract
The lysosome is an acidic organelle that is important for maintaining cellular and metabolic homeostasis in hepatocytes. Lysosomal dysfunction and chronic inflammation coexist, and both contribute to obesity-associated hepatic insulin resistance. However, in the context of obesity, the interplay between inflammatory signals and hepatic lysosomal function remains largely unknown. Inducible nitric oxide synthase (iNOS) is a hallmark for inflammation, and is activated in obesity. The aim of this study is to understand the molecular link between iNOS-mediated lysosomal nitric oxide (NO) production, hepatic lysosomal function, and autophagy in the context of obesity-associated insulin resistance.
The role of iNOS in hepatic autophagy, as related to insulin and glucose homeostasis were studied in mice with diet-induced obesity (DIO). The effects and mechanisms of iNOS-mediated lysosomal NO production on lysosomal function and hepatic autophagy were studied in primary hepatocytes as well as in a mouse model of DIO.
We demonstrate that obesity promotes iNOS localization to the lysosome and decreases levels of lysosomal arginine, resulting in an accumulation of NO in hepatic lysosomes. This lysosomal NO production is attenuated by treatment with a NO scavenger, while co-overexpression of mTOR and a lysosomal arginine transporter (SLC38A9) enhances lysosomal NO production and suppresses autophagy. In addition, we show that deletion of iNOS ameliorates lysosomal nitrosative stress in the livers of DIO mice, promotes lysosomal biogenesis by activating transcription factor EB (TFEB), and enhances lysosomal function and autophagy. Lastly, deletion of iNOS in mice with DIO improves hepatic insulin sensitivity, which is diminished by suppression of TFEB or autophagy related 7 (Atg7).
Our studies suggest that lysosomal iNOS-mediated NO signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.
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Details
- Title: Subtitle
- Hepatic Lysosomal iNOS Activity Impairs Autophagy in Obesity
- Creators
- Qingwen Qian - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IowaZeyuan Zhang - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IowaMark Li - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IowaKalie Savage - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IowaDechun Cheng - Department of Parasitology, Harbin Medical School, Harbin, ChinaAdam J Rauckhorst - Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center, Fraternal Order of Eagles Diabetes Research Center Metabolomics Core, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IowaJames A Ankrum - Roy J. Carver Department of Biomedical Engineering, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa College of Engineering, Iowa City, IowaEric B Taylor - Department of Biochemistry, Fraternal Order of Eagles Diabetes Research Center, Fraternal Order of Eagles Diabetes Research Center Metabolomics Core, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, IowaWen-xing Ding - Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KansasYi Xiao - State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian, ChinaHuo-jun Cao - Departments of Endodontics, University of Iowa College of Dentistry, Iowa City, IowaLing Yang - Department of Anatomy and Cell Biology, Fraternal Order of Eagles Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa Carver College of Medicine, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- Cellular and molecular gastroenterology and hepatology, Vol.8(1), pp.95-110
- DOI
- 10.1016/j.jcmgh.2019.03.005
- PMID
- 30926581
- PMCID
- PMC6522853
- NLM abbreviation
- Cell Mol Gastroenterol Hepatol
- ISSN
- 2352-345X
- eISSN
- 2352-345X
- Publisher
- Elsevier Inc
- Grant note
- 1-18-PDF-060; R01 DK104998; R01 AA020518; R01 DK102142; U01 AA024733; P20GM103549; P30GM118247 / American Diabetes Association Postdoctoral 1-18-IBS-149; R01 DK108835-01A1 / American Diabetes Association Innovative Basic Science 15SDG25510016 / American Heart Association Scientist Development 19PRE34380258 / American Heart Association Predoctoral
- Language
- English
- Date published
- 2019
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Endodontics; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984000923102771
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