title: Peroxisome proliferator-activated receptor gamma overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells.
abstract: 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 (PPARgamma), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARgamma ligands, however, are at least in part mediated through PPARgamma-independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARgamma in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)-regulated PPARgamma overexpression. Induction of PPARgamma expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARgamma-overexpressing cells synthesised less collagen than controls. To monitor effects of PPARgamma on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up- and 19 down-regulated genes in PPARgamma-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 PPARgamma in the induction of a quiescent PSC phenotype. PPARgamma-regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies.
authors.affiliation: Department of Medicine, Division of Gastroenterology, Medical Faculty, University of Rostock, Rostock, 18057, Germany. jaster@med.uni-rostock.de
authors.forename: Robert
authors.initials: R
authors.lastname: Jaster
authors.forename: Philipp
authors.initials: P
authors.lastname: Lichte
authors.forename: Brit
authors.initials: B
authors.lastname: Fitzner
authors.forename: Peter
authors.initials: P
authors.lastname: Brock
authors.forename: Anne
authors.initials: A
authors.lastname: Glass
authors.forename: Thomas
authors.initials: T
authors.lastname: Karopka
authors.forename: Lothar
authors.initials: L
authors.lastname: Gierl
authors.forename: Dirk
authors.initials: D
authors.lastname: Koczan
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Thiesen
authors.forename: Gisela
authors.initials: G
authors.lastname: Sparmann
authors.forename: Jörg
authors.initials: J
authors.lastname: Emmrich
authors.forename: Stefan
authors.initials: S
authors.lastname: Liebe
mesh_terms: D000818:Animals; D002460:Cell Line; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D047495:PPAR gamma / Q000235:genetics*; D010179:Pancreas / Q000166:cytology* / Q000187:drug effects; D051381:Rats
chemical_list: D005343:Fibrinolytic Agents; D047495:PPAR gamma