Ligands of peroxisome proliferator-activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells

Background&Aims: Proliferation and migration of hepatic stellate cells (HSC s) and expression of chemokines are involved in the pathogenesis of liver i nflammation and fibrogenesis. Peroxisome proliferator-activated receptor (P PAR)-gamma is a receptor transcription factor that controls growth and diff erentiation in different tissues. We explored the effects of PPAR-gamma ago nists on the biological actions of cultured human HSCs. Methods: HSCs were isolated from normal human liver tissue and used in their myofibroblast-lik e phenotype or immediately after isolation. Activation of PPAR-gamma was in duced with 15-deoxy-Delta(12,14)-prostaglandin J(2) or with troglitazone. R esults: PPAR-gamma agonists dose-dependently inhibited HSC proliferation an d chemotaxis induced by platelet-derived growth factor. This effect was ind ependent of changes in postreceptor signaling or expression of c-fos and c- myc and was associated with inhibition of cell cycle progression beyond the G(1) phase. Activation of PPAR-gamma also resulted in a complete inhibitio n of the expression of monocyte chemotactic protein 1 at the gene and prote in levels. Comparison of quiescent and culture-activated HSCs revealed a ma rked decrease in PPAR-gamma expression in activated cells. Conclusions: Act ivation of PPAR-gamma modulates profibrogenic and pro-inflammatory actions in HSCs. Reduced PPAR-gamma expression may contribute to confer an activate d phenotype to HSCs.