Titre :

GW501516-activated PPARbeta/delta promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation.

Auteur(s) :

Kostadinova, Radina [Auteur]
Center for Integrative Genomics - Institute of Bioinformatics, Génopode [CIG]
Montagner, Alexandra [Auteur]
ToxAlim [ToxAlim]
Center for Integrative Genomics - Institute of Bioinformatics, Génopode [CIG]
Gouranton, Erwan [Auteur]
Center for Integrative Genomics - Institute of Bioinformatics, Génopode [CIG]
Fleury, Sébastien [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Guillou, Hervé [Auteur]
Toxicologie Intégrative & Métabolisme [ToxAlim-TIM]
Dombrowicz, David [Auteur]
Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD]
Desreumaux, Pierre [Auteur]
Institut Mondor de Recherche Biomédicale [IMRB]
Wahli, Walter [Auteur correspondant]
Center for Integrative Genomics - Institute of Bioinformatics, Génopode [CIG]

Titre de la revue :

Cell & Bioscience

Pagination :

34

Éditeur :

BioMed Central

Date de publication :

2012-10-10

ISSN :

2045-3701

Mot(s)-clé(s) en anglais :

Peroxisome proliferator-activated receptor β/δ
Inflammation
Fibrosis
Signaling pathways

Discipline(s) HAL :

Sciences du Vivant [q-bio]/Biologie cellulaire

Résumé en anglais : [en]

ABSTRACT: BACKGROUND: After liver injury, the repair process comprises activation and proliferation of hepatic stellate cells (HSCs), which produce extracellular matrix (ECM) proteins. Peroxisome proliferator-activated ...
Lire la suite >ABSTRACT: BACKGROUND: After liver injury, the repair process comprises activation and proliferation of hepatic stellate cells (HSCs), which produce extracellular matrix (ECM) proteins. Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is highly expressed in these cells, but its function in liver repair remains incompletely understood. This study investigated whether activation of PPARbeta/delta with the ligand GW501516 influenced the fibrotic response to injury from chronic carbon tetrachloride (CCl4) treatment in mice. Wild type and PPARbeta/delta-null mice were treated with CCl4 alone or CCl4 co-administered with GW501516. To unveil mechanisms underlying the PPARbeta/delta-dependent effects, we analyzed the proliferative response of human LX-2 HSCs to GW501516 in the presence or absence of PPARbeta/delta. RESULTS: We found that GW501516 treatment enhanced the fibrotic response. Compared to the other experimental groups, CCl4/GW501516-treated wild type mice exhibited increased expression of various profibrotic and pro-inflammatory genes, such as those involved in extracellular matrix deposition and macrophage recruitment. Importantly, compared to healthy liver, hepatic fibrotic tissues from alcoholic patients showed increased expression of several PPAR target genes, including phosphoinositide-dependent kinase-1, transforming growth factor beta-1, and monocyte chemoattractant protein-1. GW501516 stimulated HSC proliferation that caused enhanced fibrotic and inflammatory responses, by increasing the phosphorylation of p38 and c-Jun N-terminal kinases through the phosphoinositide-3 kinase/protein kinase-C alpha/beta mixed lineage kinase-3 pathway. CONCLUSIONS: This study clarified the mechanism underlying GW501516-dependent promotion of hepatic repair by stimulating proliferation of HSCs via the p38 and JNK MAPK pathways.Lire moins >

Langue :

Anglais

Comité de lecture :

Oui

Audience :

Internationale

Vulgarisation :

Non

Projet Européen :

Molecular Targets Open for Regulation by the gut flora – New Avenues for improved Diet to Optimize European health

Collections :

• Récepteurs nucléaires, Maladies Cardiovasculaires et Diabète (RNMCD) - U1011

Source :

Harvested from HAL