Peroxisome proliferator - activated receptor ? 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 (PPARγ), such as thiazolidinediones, are potent inhibitors of stellate cell activation and fibrogenesis in pancreas and liver. The effects of PPARγ ligands, however, however, are at least in part mediated through PPARγ‐independent pathways. Here, we have chosen a different approach to study regulatory functions of PPARγ in PSCs. Using immortalised rat PSCs, we have established a model of tetracycline (tet)‐regulated PPARγ over‐expression. Induction of PPARγ expression strongly inhibited proliferation and enhanced the rate of apoptotic cell death. Furthermore, PPARγ‐overexpressing cells synthesised less collagen than controls. To monitor effects of PPARγ on PSC gene expression, we employed Affymetrix microarray technology. Using stringent selection criteria, we identified 21 up‐ and 19 down‐regualated genes in PPARγ‐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 differentition. In conclusion, our data suggest an active role of PPARγ in the induction of a quiescent PSC phenotype. PPARγ‐regulated genes in PSCs may serve as novel targets for the development of antifibrotic therapies.

Peroxisome Proliferator-activated Receptor γ Interacts with CIITA·RFX5 Complex to Repress Type I Collagen Gene Expression

“…Recent reports demonstrate that PPAR␥, a member of the nuclear receptor superfamily, acts as a repressor of type I collagen synthesis (16,17,33). Our data confirm that exogenously expressed PPAR␥ down-regulates collagen expression in a dose-responsive manner in human lung fibroblast cells as well as human aortic smooth muscle cells.…”

“…The thiazolidinedione compounds and certain prostaglan- dins have been used to demonstrate that activation of PPAR␥ inhibits collagen synthesis (18) and fibrosis in lung (14,15,19,57), kidney (8,9,58), liver (10,11,33,36,59), cardiac fibroblasts (60), and skin (61). The issue of endogenous ligand for PPAR␥ in cells has been controversial.…”

The pancreatic stellate cell: a star on the rise in pancreatic diseases

“…PDGF, and the PPARγ ligand PGJ 2 in a manner similar to that of their cultured primary cell counterparts (34)(35)(36). The combined use of cultured primary PaSCs and immortalized cells, coupled with the use of coculture systems (for example, coculture of acinar cells and PaSCs), is likely to provide additional mechanistic insights into the biology of PaSCs.…”

“…There are also several reports from in vitro experiments using PaSCs that show key roles in the activation and/or proliferation process for MAPK pathways, in particular, ERK1/2, p38 kinase, and JNK (50,52,53,66,109,110); PI3K and PKC (111); PPARγ (36,112); NADPH oxidases (our unpublished observations); and ethanol metabolism to acetaldehyde (18). In these studies, inhibition of most of these pathways results in attenuation of the activation and proliferation of PaSCs, but activation of PPARγ seems to block PaSC activation (36,112). It has also been reported that activated rat PaSCs express COX-2 when stimulated with TGF-β 1 and other cytokines (45), as well as when stimulated with conditioned media from human pancreatic tumor cells (113).…”

Signal transduction in pancreatic stellate cells

“…Because PSCs lose their adiopogenic properties upon activation, negative regulation of PPAR-c signaling is likely to be associated with PSCs activation. Studies using PPAR-c ligands and overexpression of PPAR-c have implicated this pathway in the maintenance of PSCs quiescence [37,38]. PPAR-c ligands inhibited proliferation, MCP-1 production, collagen synthesis, and a-SMA expression in PSCs [37].…”