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

Abstract

Background & Aims: Proliferation and migration of hepatic stellate cells (HSCs) and expression of chemokines are involved in the pathogenesis of liver inflammation and fibrogenesis. Peroxisome proliferator–activated receptor (PPAR)-γ is a receptor transcription factor that controls growth and differentiation in different tissues. We explored the effects of PPAR-γ agonists on the biological actions of cultured human HSCs. Methods: HSCs were isolated from normal human liver tissue and used in their myofibroblast-like phenotype or immediately after isolation. Activation of PPAR-γ was induced with 15-deoxy-Δ12,14-prostaglandin J2 or with troglitazone. Results: PPAR-γ agonists dose-dependently inhibited HSC proliferation and chemotaxis induced by platelet-derived growth factor. This effect was independent of changes in postreceptor signaling or expression of c-fos and c-myc and was associated with inhibition of cell cycle progression beyond the G1 phase. Activation of PPAR-γ also resulted in a complete inhibition of the expression of monocyte chemotactic protein 1 at the gene and protein levels. Comparison of quiescent and culture-activated HSCs revealed a marked decrease in PPAR-γ expression in activated cells. Conclusions: Activation of PPAR-γ modulates profibrogenic and proinflammatory actions in HSCs. Reduced PPAR-γ expression may contribute to confer an activated phenotype to HSCs.GASTROENTEROLOGY 2000;119:466-478