Journal article
Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation
JCI insight, Vol.2(24), e96184
12/21/2017
DOI: 10.1172/jci.insight.96184
PMCID: PMC5752273
PMID: 29263294
Abstract
Cardiac hypertrophic remodeling during chronic hemodynamic stress is associated with a switch in preferred energy substrate from fatty acids to glucose, usually considered to be energetically favorable. The mechanistic interrelationship between altered energy metabolism, remodeling, and function remains unclear. The ROS-generating NADPH oxidase-4 (Nox4) is upregulated in the overloaded heart, where it ameliorates adverse remodeling. Here, we show that Nox4 redirects glucose metabolism away from oxidation but increases fatty acid oxidation, thereby maintaining cardiac energetics during acute or chronic stresses. The changes in glucose and fatty acid metabolism are interlinked via a Nox4-ATF4–dependent increase in the hexosamine biosynthetic pathway, which mediates the attachment of O-linked N-acetylglucosamine (O-GlcNAcylation) to the fatty acid transporter CD36 and enhances fatty acid utilization. These data uncover a potentially novel redox pathway that regulates protein O-GlcNAcylation and reprograms cardiac substrate metabolism to favorably modify adaptation to chronic stress. Our results also suggest that increased fatty acid oxidation in the chronically stressed heart may be beneficial.
Details
- Title: Subtitle
- Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation
- Creators
- Adam A Nabeebaccus - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomAnna Zoccarato - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomAnne D Hafstad - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomCelio X.C Santos - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomEllen Aasum - Cardiovascular Research Group, Department of Medical Biology, UiT The Arctic University of Norway, Tromsø, NorwayAlison C Brewer - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomMin Zhang - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomMatteo Beretta - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomXiaoke Yin - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomJames A West - Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United KingdomKatrin Schröder - Institut für Kardiovaskuläre Physiologie, Goethe-Universität, Frankfurt am Main, GermanyJulian L Griffin - Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, Cambridge, United KingdomThomas R Eykyn - Division of Imaging Sciences & Biomedical Engineering, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomE. Dale Abel - Department of Medicine and Fraternal Order of Eagles Diabetes Research Center, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAManuel Mayr - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United KingdomAjay M Shah - Cardiovascular Division, King’s College London British Heart Foundation Centre of Excellence, London, United Kingdom
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.2(24), e96184
- DOI
- 10.1172/jci.insight.96184
- PMID
- 29263294
- PMCID
- PMC5752273
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Grant note
- RG/13/11/30384; RE/13/2/30182 / ; MC_UP_A90_1006 / ;
- Language
- English
- Date published
- 12/21/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984024541302771
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