TNF-α reduces PGC-1α expression through NF-κB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model

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

doi:10.1093/cvr/cvn327

Cited by 149 publications

(119 citation statements)

References 41 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…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

View full text Add to dashboard Cite

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.

show abstract

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

View full text Add to dashboard Cite

show abstract

“…RNA preparation and quantitative RT-PCR The relative levels of specific mRNAs were assessed by real-time RT-PCR, as previously described [27] (see electronic supplementary material [ESM] Table 1 for primers used). XBP1 splicing (sXBP1) was examined by gel electrophoresis as previously reported [28].…”

Section: Methodsmentioning

confidence: 99%

“…Isolation of nuclear extracts and electrophoretic mobility shift assay The isolation of nuclear extracts and electrophoretic mobility shift assay (EMSA) were performed as described elsewhere [27].…”

Section: -Deoxy-d-[mentioning

confidence: 99%

Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

et al. 2013

View full text Add to dashboard Cite

Aims/hypothesis Although the substitution of saturated fatty acids with oleate has been recommended in the management of type 2 diabetes mellitus, the mechanisms by which oleate improves insulin resistance in skeletal muscle cells are not completely known. Here, we examined whether oleate, through activation of AMP-activated protein kinase (AMPK), prevented palmitate-induced endoplasmic reticulum (ER) stress, which is involved in the link between lipid-induced inflammation and insulin resistance. Methods Studies were conducted in mouse C2C12 myotubes and in the human myogenic cell line LHCN-M2. To analyse the involvement of AMPK, activators and inhibitors of this kinase and overexpression of a dominant negative AMPK construct (K45R) were used. Results Palmitate increased the levels of ER stress markers, whereas oleate did not. In palmitate-exposed cells incubated with a lower concentration of oleate, the effects of palmitate were prevented. The induction of ER stress markers by palmitate was prevented by the presence of the AMPK activators AICAR and A-769662. Moreover, the ability of oleate to prevent palmitate-induced ER stress and inflammation (nuclear factor-kappa B [NF-κB] DNA-binding activity and expression and secretion of IL6) as well as insulinstimulated Akt phosphorylation and 2-deoxyglucose uptake was reversed in the presence of the AMPK inhibitor compound C or by overexpression of a dominant negative AMPK construct. Finally, palmitate reduced phospho-AMPK levels, whereas this was not observed in oleateexposed cells or in palmitate-exposed cells supplemented with oleate. Conclusions/interpretation Overall, these findings indicate that oleate prevents ER stress, inflammation and insulin resistance in palmitate-exposed skeletal muscle cells by activating AMPK.

show abstract

“…In heart, kidney, and liver, PGC-1, ERR and MCAD mRNA was markedly reduced 16h after LPS injection [279]. Furthermore, in cardiac tissue, inflammation-dependent PGC-1 repression was further confirmed in vitro and in vivo, which could be rescued by inhibiting the NF-B pathway [280][281][282]. Sepsisassociated acute kidney injury is associated with swollen, dysfunctional mitochondria and reduced PGC-1 levels that correlate with renal impairment [283].…”

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

confidence: 95%

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

Eisele

Handschin

2013

Semin Immunopathol

View full text Add to dashboard Cite

(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.

show abstract

TNF-α reduces PGC-1α expression through NF-κB and p38 MAPK leading to increased glucose oxidation in a human cardiac cell model

Abstract: These results point to PGC-1alpha downregulation as a potential contributor to cardiac dysfunction and heart failure in metabolic disorders with an inflammatory background.

Cited by 149 publications

References 41 publications

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

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

Oleate prevents saturated-fatty-acid-induced ER stress, inflammation and insulin resistance in skeletal muscle cells through an AMPK-dependent mechanism

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

Contact Info

Product

Resources

About