Peroxisome proliferator-activated receptor γ overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells

Pancreatic stellate cells (PSCs) play a key role in the development of pancreatic fibrosis, a constant feature of chronic pancreatitis and pancreatic cancer. In response to pro-fibrogenic mediators, PSCs undergo an activation process that involves proliferation, enhanced production of extracellular matrix proteins and a phenotypic transition towards myofibroblasts. Ligands of the peroxisome proliferator-activated receptor gamma (PPAR gamma), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPAR gamma ligands, however, are at least in part mediated through PPAR gamma independent pathways. Here, we have chosen a different approach to study regulatory functions of PPAR gamma in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)-regulated PPAR gamma overexpression. Induction of PPAR gamma expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPAR gamma overexpressing cells synthesised less collagen than controls. To monitor effects of PPAR gamma on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up-and 19 down-regulated genes in PPAR gamma overexpressing cells. Most of the corresponding gene products are either involved in lipid metabolism, play a role in signal transduction, or are secreted molecules that regulate cell growth and differentiation. In conclusion, our data suggest an active role of PPAR gamma in the induction of a quiescent PSC phenotype. PPAR gamma regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies.