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

TY - JOUR

T1 - Nox4 reprograms cardiac substrate metabolism via protein O-GlcNAcylation to enhance stress adaptation

AU - Nabeebaccus, Adam A

AU - Zoccarato, Anna

AU - Hafstad, Anne D

AU - Santos, Celio Xc

AU - Aasum, Ellen

AU - Brewer, Alison C

AU - Zhang, Min

AU - Beretta, Matteo

AU - Yin, Xiaoke

AU - West, James A

AU - Schröder, Katrin

AU - Griffin, Julian L

AU - Eykyn, Thomas R

AU - Abel, E Dale

AU - Mayr, Manuel

AU - Shah, Ajay M

PY - 2017/12/21

Y1 - 2017/12/21

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/jci.insight.96184

DO - 10.1172/jci.insight.96184

M3 - Article

C2 - 29263294

SN - 2379-3708

VL - 2

SP - 1

EP - 16

JO - JCI Insight

JF - JCI Insight

IS - 24

M1 - 10.1172/jci.insight.96184

ER -