title: GW501516-activated PPARβ/δ promotes liver fibrosis via p38-JNK MAPK-induced hepatic stellate cell proliferation.
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 (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.
authors.affiliation: Center for Integrative Genomics, National Research Center Frontiers in Genetics, University of Lausanne, Genopode Building, 1015, Lausanne, Switzerland. walter.wahli@unil.ch.
authors.forename: Radina
authors.initials: R
authors.lastname: Kostadinova
authors.forename: Alexandra
authors.initials: A
authors.lastname: Montagner
authors.forename: Erwan
authors.initials: E
authors.lastname: Gouranton
authors.forename: Sébastien
authors.initials: S
authors.lastname: Fleury
authors.forename: Hervé
authors.initials: H
authors.lastname: Guillou
authors.forename: David
authors.initials: D
authors.lastname: Dombrowicz
authors.forename: Pierre
authors.initials: P
authors.lastname: Desreumaux
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli