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Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation

Research output: Contribution to journalArticle

Adam A Nabeebaccus, Anna Zoccarato, Anne D Hafstad, Celio Xc Santos, Ellen Aasum, Alison C Brewer, Min Zhang, Matteo Beretta, Xiaoke Yin, James A West, Katrin Schröder, Julian L Griffin, Thomas R Eykyn, E Dale Abel, Manuel Mayr, Ajay M Shah

Original languageEnglish
JournalJCI Insight
Volume2
Issue number24
Early online date21 Dec 2017
DOIs
Publication statusE-pub ahead of print - 21 Dec 2017

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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.

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