Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
Volume 1811, Issue 2, Pages 59-67Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbalip.2010.11.002
Keywords
High-fat diet; Inflammation; Heart; NF-kappa B; Nuclear factor-kappa B; Peroxisome proliferator-activated receptor
Funding
- Ministerio de Ciencia e Innovacion of the Spanish Government [SAF2006-01475, SAF2009-06939]
- Swiss National Science Foundation
- Spanish Government [FPI BES2005-8448]
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Owing to its high fat content, the classical Western diet has a range of adverse effects on the heart, including enhanced inflammation, hypertrophy, and contractile dysfunction. Proinflammatory factors secreted by cardiac cells, which are under the transcriptional control of nuclear factor-kappa B (NF-kappa B), may contribute to heart failure and dilated cardiomyopathy. The underlying mechanisms are complex, since they are linked to systemic metabolic abnormalities and changes in cardiomyocyte phenotype. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate metabolism and are capable of limiting myocardial inflammation and hypertrophy via inhibition of NF-kappa B. Since PPAR beta/delta is the most prevalent PPAR isoform in the heart, we analyzed the effects of the PPAR beta/delta agonist GW501516 on inflammatory parameters. A high-fat diet induced the expression of tumor necrosis factor-alpha, monocyte chemoattractant protein-1, and interleukin-6, and enhanced the activity of NF-kappa B in the heart of mice. GW501516 abrogated this enhanced proinflammatory profile. Similar results were obtained when human cardiac AC16 cells exposed to palmitate were coincubated with GW501516. PPAR beta/delta activation by GW501516 enhanced the physical interaction between PPAR beta/delta and p65, which suggests that this mechanism may also interfere NF-kappa B transactivation capacity in the heart. GW501516-induced PPAR beta/delta activation can attenuate the inflammatory response induced in human cardiac AC16 cells exposed to the saturated fatty acid palmitate and in mice fed a high-fat diet. This is relevant, especially taking into account that PPAR beta/delta has been postulated as a potential target in the treatment of obesity and the insulin resistance state. (C) 2010 Elsevier B.V. All rights reserved.
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