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

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.This study clarified the mechanism underlying GW501516-dependent promotion of hepatic repair by stimulating proliferation of HSCs via the p38 and JNK MAPK pathways.Chronic liver disease represents an important cause of mortality and morbidity. Repeated and/or chronic injury exacerbates wound healing and tissue remodeling processes, leading to progressive fibrosis and, ultimately, end-stage cirrhosis. Currently, the only effective treatment for end-stage cirrhosis is liver transplantation [1]. Therefore, therapeutic interventions that block early stage progression of hepatic fibrosis are important for the prevention of liver cirrhosis. In wounded areas, HSCs are stimulated by factors that promote proliferation and transition from a quiescent, lipid/vitamin A-storing phenotype towards an activated, proliferative myofibroblast-like phenotype. Activated HSCs synthesize alpha-smooth muscle actin (α-SMA), various cytokines, chemokines, growth factors, and fibroblastic cell markers. In addition, they produce abnormally high levels of ECM proteins and remodeling factors, which eventually results in matrix accumulation [2,3]. However, the signali