Peroxisome proliferator-activated receptor γ overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells
Peroxisome proliferator-activated receptor γ overexpression inhibits pro-fibrogenic activities of immortalised rat pancreatic stellate cells
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DOI：
10.1111/j.1582-4934.2005.tb00497.x
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发表时间：
2005-07-01
影响因子：
5.3
通讯作者：
Liebe, S
中科院分区：
文献类型：
--
作者：
Jaster, R;Lichte, P;Liebe, S
胰腺星状细胞（PSCs）在胰腺纤维化的发展中起关键作用，胰腺纤维化是慢性胰腺炎和胰腺癌的一个恒定特征。在促纤维化介质的作用下，PSCs经历了一个激活过程，包括增殖、细胞外基质蛋白的增强产生和向肌成纤维细胞的表型转变。过氧化物酶体增殖物激活受体γ (PPAR γ)的配体，如噻唑烷二酮，是胰腺和肝脏中星状细胞活化和纤维生成的有效抑制剂。然而，PPAR γ配体的作用至少部分是通过PPAR γ非依赖性途径介导的。在这里，我们选择了一种不同的方法来研究PPAR γ在psc中的调节功能。利用永生化大鼠PSCs，我们建立了四环素（tet）调控PPAR γ过表达的模型。诱导PPAR γ表达可明显抑制细胞增殖，提高凋亡细胞的死亡率。此外，PPAR γ过表达的细胞合成的胶原蛋白比对照组少。为了监测PPAR γ对PSC基因表达的影响，我们采用Affymetrix微阵列技术。通过严格的筛选标准，我们在PPAR γ过表达细胞中鉴定出21个上调和19个下调的基因。大部分相应的基因产物要么参与脂质代谢，要么参与信号转导，要么是调节细胞生长和分化的分泌分子。总之，我们的数据表明PPAR γ在诱导静止PSC表型中的积极作用。PSCs中PPAR γ调节基因可能成为抗纤维化治疗的新靶点。
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.