GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation

Cell & Bioscience

Walter Wahli⁵  Pierre Desreumaux²  David Dombrowicz¹  Hervé Guillou⁴  Sébastien Fleury¹  Erwan Gouranton⁵  Alexandra Montagner⁴  Radina Kostadinova³ 

[1] Inserm U1011, Institut Pasteur de Lille, 1, University of Lille Nord, rue Prof. Calmette, BP245, 59019, Lille Cedex, France;Inserm U 995, Department of Gastroenterology CHU Lille, University of Lille Nord, 59019, Lille Cedex, France;Present address: Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070, Basel, Switzerland;INRA ToxAlim, Integrative Toxicology and Metabolism, UMR1331, 180, Chemin de Tournefeuille, BP 93173, 31027, Toulouse Cedex 3, France;Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Genopode Building, 1015, Lausanne, Switzerland

关键词: Proliferation;    Signaling pathways;    Fibrosis;    Inflammation;    Peroxisome proliferator-activated receptor β/δ;   

Others  :  793148
DOI  :  10.1186/2045-3701-2-34

 received in 2012-08-24, accepted in 2012-10-04,  发布年份 2012

【 摘 要 】

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 (PPARβ/δ) is highly expressed in these cells, but its function in liver repair remains incompletely understood. This study investigated whether activation of PPARβ/δ with the ligand GW501516 influenced the fibrotic response to injury from chronic carbon tetrachloride (CCl₄) treatment in mice. Wild type and PPARβ/δ-null mice were treated with CCl₄ alone or CCl₄ co-administered with GW501516. To unveil mechanisms underlying the PPARβ/δ-dependent effects, we analyzed the proliferative response of human LX-2 HSCs to GW501516 in the presence or absence of PPARβ/δ.

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.

【 授权许可】

   
2012 Kostadinova et al.; licensee BioMed Central Ltd.

【 图 表 】

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