Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro
Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro
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DOI：
10.1053/gast.2002.33666
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发表时间：
2002-06-01
期刊：
影响因子：
29.4
通讯作者：
Casini, A
中科院分区：
文献类型：
--
作者：
Galli, A;Crabb, DW;Casini, A
背景和目标：配体依赖性转录因子过氧化物酶体增殖物激活受体γ（PPAR-gamma）在肝星状细胞（HSC）中表达，其转录活性在培养的细胞转分化过程中降低。PPARgamma转录激活降低血小板衍生生长因子诱导的HSC增殖并抑制α-平滑肌肌动蛋白表达本研究的目的是评估口服合成的PPARgamma配体噻唑烷二酮（TZD）是否可能影响肝纤维化动物模型中的胶原沉积。方法：在大鼠中测试2 TZD（吡格列酮或罗格列酮）对通过毒素施用（二甲基亚硝胺或四氯化碳）或胆管结扎诱导的肝纤维化的作用。使用从对照和处理的大鼠分离的HSC的核提取物，通过凝胶移位测定评价体内PPAR-gamma活化。结果：TZD口服给药可减少肝纤维化毒性和胆汁淤积模型中细胞外基质沉积和HSC活化。与对照组大鼠的HSC相比，从纤维化大鼠分离的HSC的核提取物中PPAR-gamma特异性DNA结合显著受损。TZD给药恢复了HSC核中的PPAR-gamma DNA结合。在体外，TZD诱导的PPARgamma激活抑制胶原蛋白和纤维连接蛋白的合成诱导的转化生长因子（TGF）-β 1在人HSC中，通过酶联免疫吸附试验和Northen印迹。TZD还降低了TGF-β 1诱导的3.5-β-淀粉酶前胶原I型启动子在人HSC中转染的活性。结论：这些发现表明HSC中的PPAR-gamma活化延缓体内纤维化，并提示TZD用于治疗肝纤维化。
Background & Aims: The ligand-dependent transcription factor peroxisome proliferator-activated receptor gamma (PPAR-gamma) is expressed in hepatic stellate cells (HSC), and its transcriptional activity Is reduced during cell transdifferentiation In culture. PPARgamma transcriptional activation decreases platelet-derived growth factor-induced proliferation and inhibits alpha-smooth muscle actin expression In cultured HSC. The aim of our study was to evaluate whether oral administration of synthetic PPARgamma ligands, thiazolidinediones (TZD), might affect collagen deposition In animal models of liver fibrosis' Methods: The effect of 2 TZD (pioglitazone or rosiglitazone) was tested on liver fibrosis Induced In rats by either toxin administration (dimethylnitrosamine or carbon tetrachloride) or bile duct ligation. In vivo PPAR-gamma activation was evaluated by gel shift assay using nuclear extracts from HSC Isolated from control and treated rats. Results: Oral administration of TZD reduced extracellular matrix deposition and HSC activation In both toxic and cholestatic models of liver fibrosis. PPAR-gamma-specific DNA binding was significantly impaired in nuclear extracts of HSC isolated from fibrotic rats compared with HSC from control rats. TZD administration restored PPAR-gamma DNA binding In HSC nuclei. In vitro, TZD-induced PPARgamma activation Inhibited collagen and fibronectin synthesis induced by transforming growth factor (TGF)-beta1 in human HSC, as measured by enzyme-linked Immunosorbent assay and Northen blotting. TZD also reduced the TGF-beta1-induced activity of a 3.5-kilobase procollagen type I promoter transfected In human HSC. Conclusions: These findings indicate that PPAR-gamma activation In HSC retards fibrosis In vivo and suggest the use of TZD for the treatment of liver fibrosis.