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The Role of Peroxisome Proliferator-Activated Receptor beta/delta on the Inflammatory Basis of Metabolic Disease.

Coll T, Barroso E, Alvarez-Guardia D, Serrano L, Salvadó L, Merlos M, Palomer X, Vázquez-Carrera M - PPAR Res (2010)

Bottom Line: The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation.Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects.PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutic Chemistry, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Faculty of Pharmacy, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain.

ABSTRACT
The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects. PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPARbeta/delta ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPARbeta/delta ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases.

No MeSH data available.


Related in: MedlinePlus

Molecular mechanisms of Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are ligand-activated transcription factors that regulate gene expression through two mechanisms: transactivation and transrepression. In transactivation, PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which are located in the promoter regions of genes involved in glucose and fatty acid metabolism. PPARs may also regulate gene expression through a DNA-independent mechanism called transrepression. Through this mechanism, PPARs inhibit the activity of several transcription factors such as Nuclear Factor-κB, which leads to anti-inflammatory effects. STAT denotes signal transducers and activators of transcription, IS-GFRE is the interferon-stimulated gene factor responsive element, and TRE is the TPA responsive element, where TPA is a phorbol ester.
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Related In: Results  -  Collection


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fig1: Molecular mechanisms of Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are ligand-activated transcription factors that regulate gene expression through two mechanisms: transactivation and transrepression. In transactivation, PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which are located in the promoter regions of genes involved in glucose and fatty acid metabolism. PPARs may also regulate gene expression through a DNA-independent mechanism called transrepression. Through this mechanism, PPARs inhibit the activity of several transcription factors such as Nuclear Factor-κB, which leads to anti-inflammatory effects. STAT denotes signal transducers and activators of transcription, IS-GFRE is the interferon-stimulated gene factor responsive element, and TRE is the TPA responsive element, where TPA is a phorbol ester.

Mentions: PPARs are members of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism, and inflammation [2]. To be transcriptionally active, PPARs need to heterodimerize with the 9-cis retinoic acid receptor (RXR) (NR2B) (Figure 1). PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which consist of an imperfect direct repeat of the consensus binding site for nuclear hormone receptors (AGGTCA), separated by one nucleotide (Direct Repeat 1, DR-1). These sequences have been characterized within the promoter regions of PPAR target genes. The binding occurs in such a way that PPAR is always oriented to the DNA's 5′-end, while RXR is oriented to the 3′-end. In the absence of a ligand, high-affinity complexes are formed between PPAR-RXR heterodimers and nuclear receptor corepressor proteins, which block transcriptional activation by sequestering the heterodimer from the promoter.


The Role of Peroxisome Proliferator-Activated Receptor beta/delta on the Inflammatory Basis of Metabolic Disease.

Coll T, Barroso E, Alvarez-Guardia D, Serrano L, Salvadó L, Merlos M, Palomer X, Vázquez-Carrera M - PPAR Res (2010)

Molecular mechanisms of Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are ligand-activated transcription factors that regulate gene expression through two mechanisms: transactivation and transrepression. In transactivation, PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which are located in the promoter regions of genes involved in glucose and fatty acid metabolism. PPARs may also regulate gene expression through a DNA-independent mechanism called transrepression. Through this mechanism, PPARs inhibit the activity of several transcription factors such as Nuclear Factor-κB, which leads to anti-inflammatory effects. STAT denotes signal transducers and activators of transcription, IS-GFRE is the interferon-stimulated gene factor responsive element, and TRE is the TPA responsive element, where TPA is a phorbol ester.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2913795&req=5

fig1: Molecular mechanisms of Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are ligand-activated transcription factors that regulate gene expression through two mechanisms: transactivation and transrepression. In transactivation, PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which are located in the promoter regions of genes involved in glucose and fatty acid metabolism. PPARs may also regulate gene expression through a DNA-independent mechanism called transrepression. Through this mechanism, PPARs inhibit the activity of several transcription factors such as Nuclear Factor-κB, which leads to anti-inflammatory effects. STAT denotes signal transducers and activators of transcription, IS-GFRE is the interferon-stimulated gene factor responsive element, and TRE is the TPA responsive element, where TPA is a phorbol ester.
Mentions: PPARs are members of the nuclear receptor superfamily of ligand-activated transcription factors that regulate the expression of genes involved in fatty acid uptake and oxidation, lipid metabolism, and inflammation [2]. To be transcriptionally active, PPARs need to heterodimerize with the 9-cis retinoic acid receptor (RXR) (NR2B) (Figure 1). PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which consist of an imperfect direct repeat of the consensus binding site for nuclear hormone receptors (AGGTCA), separated by one nucleotide (Direct Repeat 1, DR-1). These sequences have been characterized within the promoter regions of PPAR target genes. The binding occurs in such a way that PPAR is always oriented to the DNA's 5′-end, while RXR is oriented to the 3′-end. In the absence of a ligand, high-affinity complexes are formed between PPAR-RXR heterodimers and nuclear receptor corepressor proteins, which block transcriptional activation by sequestering the heterodimer from the promoter.

Bottom Line: The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation.Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects.PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology and Therapeutic Chemistry, CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM)-Instituto de Salud Carlos III and Institut de Biomedicina de la Universitat de Barcelona (IBUB), Faculty of Pharmacy, University of Barcelona, Diagonal 643, 08028 Barcelona, Spain.

ABSTRACT
The pathophysiology underlying several metabolic diseases, such as obesity, type 2 diabetes mellitus, and atherosclerosis, involves a state of chronic low-level inflammation. Evidence is now emerging that the nuclear receptor Peroxisome Proliferator-Activated Receptor (PPAR)beta/delta ameliorates these pathologies partly through its anti-inflammatory effects. PPARbeta/delta activation prevents the production of inflammatory cytokines by adipocytes, and it is involved in the acquisition of the anti-inflammatory phenotype of macrophages infiltrated in adipose tissue. Furthermore, PPARbeta/delta ligands prevent fatty acid-induced inflammation in skeletal muscle cells, avoid the development of cardiac hypertrophy, and suppress macrophage-derived inflammation in atherosclerosis. These data are promising and suggest that PPARbeta/delta ligands may become a therapeutic option for preventing the inflammatory basis of metabolic diseases.

No MeSH data available.


Related in: MedlinePlus