The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells

Álvarez-Guardia, David; Palomer, Xavier; Coll, Teresa; Davidson, Mercy M.; Chan, Tung O.; Feldman, Arthur M.; Laguna, Juan C.; Vázquez‐Carrera, Manuel

doi:10.1093/cvr/cvq080

Cited by 171 publications

(133 citation statements)

References 40 publications

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“…Notably, in newborns and adult Fgf21 À / À mice treated with isoproterenol, upregulation of pro-inflammatory markers was accompanied by a decrease in PGC1a expression levels. It has been previously shown that PGC1a is repressed by hypertrophic 29 and pro-inflammatory 30,31 stimuli. We show here that the inhibitory action of FGF21 on cardiac hypertrophy and inflammation was associated with the induction of PGC1a.…”

Section: Discussionmentioning

confidence: 98%

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

et al. 2013

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Fibroblast growth factor 21 is an endocrine factor, secreted mainly by the liver, that exerts metabolic actions that favour glucose metabolism. Its role in the heart is unknown. Here we show that Fgf21 À / À mice exhibit an increased relative heart weight and develop enhanced signs of dilatation and cardiac dysfunction in response to isoproterenol infusion, indicating eccentric hypertrophy development. In addition, Fgf21 À / À mice exhibit enhanced induction of cardiac hypertrophy markers and pro-inflammatory pathways and show greater repression of fatty acid oxidation. Most of these alterations are already present in Fgf21 À / À neonates, and treatment with fibroblast growth factor 21 reverses them in vivo and in cultured cardiomyocytes. Moreover, fibroblast growth factor 21 is expressed in the heart and is released by cardiomyocytes. Fibroblast growth factor 21 released by cardiomyocytes protects cardiac cells against hypertrophic insults. Therefore, the heart appears to be a target of systemic, and possibly locally generated, fibroblast growth factor 21, which exerts a protective action against cardiac hypertrophy.

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Section: Discussionmentioning

confidence: 98%

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

et al. 2013

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“…Type I and type II interferons, tumor necrosis factor, interleukin-12, energy charge, and low NAD + /NADH or oleate/ palmitate ratios have been shown to repress PGC1α expression, localization or transcriptional activity through a variety of signaling pathways (Alvarez-Guardia et al, 2010;Haghikia et al, 2015;Kauppinen et al, 2013;Kim et al, 2007b;Palomer et al, 2009;Scarpulla, 2011). PGC1α is post-translationally modified by a number of signaling pathways important in T cell biology (Akt, p38-MAPK, AMPK, SIRT1, PRMT1) (Fernandez-Marcos and Auwerx, 2011).…”

Section: Discussionmentioning

confidence: 99%

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

Scharping¹,

Menk²,

Moreci³

et al. 2016

Immunity

397

171

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SUMMARYAlthough tumor-specific T cells recognize cancer cells, they are often rendered dysfunctional due to an immunosuppressive microenvironment. Here we showed that T cells demonstrated persistent loss of mitochondrial function and mass when infiltrating murine and human tumors, an effect specific to the tumor microenvironment and not merely caused by activation. Tumor-infiltrating T cells showed a progressive loss of PPAR-gamma coactivator 1α (PGC1α), which programs mitochondrial biogenesis, induced by chronic Akt signaling in tumor-specific T cells. Reprogramming tumor-specific T cells through enforced expression of PGC1α resulted in superior intratumoral metabolic and effector function. Our data support a model in which signals in the tumor microenvironment repress T cell oxidative metabolism, resulting in effector cells with metabolic needs that cannot be met. Our studies also suggest that modulation or reprogramming of the altered metabolism of tumor-infiltrating T cells might represent a potential strategy to reinvigorate dysfunctional T cells for cancer treatment. Abstract * Correspondence: gdelgoffe@pitt.edu.

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“…In cardiomyocytes, binding of PGC-1 to p65 that increased upon TNF exposure was detected [312]. The authors propose that p65 inhibits PGC-1 activity leading to a drop in PDK4 and subsequently higher glucose oxidation rates [312]. This would fit the model of NF-B-dependent blockade of oxidative metabolism; some ambiguities concerning the exact mechanism however remain to be uncovered.…”

Section: Mutual Influence Of Inflammatory Factors and Pgc-1smentioning

confidence: 96%

“…In hepatocytes, free fatty acids induce a p50-PGC-1 interaction and binding of this complex to the IL-10 promoter however with uncertain results concerning the role of PGC-1 in regard to coactivator or corepressor activity at this site [311]. In cardiomyocytes, binding of PGC-1 to p65 that increased upon TNF exposure was detected [312]. The authors propose that p65 inhibits PGC-1 activity leading to a drop in PDK4 and subsequently higher glucose oxidation rates [312].…”

Section: Mutual Influence Of Inflammatory Factors and Pgc-1smentioning

confidence: 98%

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Eisele

Handschin

2013

Semin Immunopathol

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(150 -250 words) [165] Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferatoractivated receptor  coactivators 1 (PGC-1) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-B) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications.

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The p65 subunit of NF-κB binds to PGC-1α, linking inflammation and metabolic disturbances in cardiac cells

Abstract: On the basis of these data, we propose that p65 directly represses PGC-1alpha activity in cardiac cells, thereby leading to a reduction in pyruvate dehydrogenase kinase 4 (PDK4) expression and the subsequent increase in glucose oxidation observed during the proinflammatory state.

Cited by 171 publications

References 40 publications

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

Fibroblast growth factor 21 protects against cardiac hypertrophy in mice

The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

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