Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells

During liver injury, hepatic stellate cells (HSC) acquire a myofibroblast-l ike phenotype associated with reduction of lipid droplets, increased collag en synthesis, and proliferation. Peroxisome proliferator-activated receptor gamma (PPAR gamma) regulates adipocyte differentiation and controls gene t ranscription in response to various activators including prostanoids and an tidiabetic thiazolidinediones. We explored whether the presence of PPAR gam ma and its transcriptional activity were involved in control of HSC prolife ration in vitvo., PPAR gamma ligands, 15-deoxy-Delta(12,14) prostaglandin J (2) (15d-PGJ(2)) and ciglitizone, significantly decrease platelet-derived g rowth factor (PDGF)-induced proliferation in activated human HSC and inhibi t alpha smooth muscle actin (alpha-SMA) expression during HSC transdifferen tiation. Treatment with 9-cis retinoic acid (9-cisRA) and LG268, ligands of the heterodimerization partner retinoic X receptor (RXR), had a negligible effect in PDGF-treated cells but caused a further reduction of proliferati on when used in combination with ciglitizone. Transfection experiments with a reporter gene consisting of 3 copies of a PPAR response element (peroxis ome proliferator response element [PPRE](3)-tk-luciferase) showed a progres sive reduction of PPAR transcriptional activity during plastic-induced HSC transdifferentiation, Cotransfection with human PPAR gamma expression vecto r restored the PPRE3-tk-luciferase reporter expression and the increased le vel of the receptor in activated HSC-inhibited cell proliferation in a dose -dependent manner. Incubation of human PPAR gamma-cotransfected HSC with PD GF strongly inhibited luciferase activity and this effect was blocked by th e inhibition of the mitogen-activated protein (MAP) kinase signal cascade. Our results indicate that depression of PPAR gamma expression and activity is involved in HSC proliferation and that the PPAR gamma ligand-mediated ac tivation exerts a previously unrecognized inhibition of PDGF-induced mitoge nesis in activated human HSC.