Zhao Caiyan, Chen Wei, Yang Liu, Chen Lihong, Stimpson Stephen A, Diehl Anna Mae
Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Biochem Biophys Res Commun. 2006 Nov 17;350(2):385-91. doi: 10.1016/j.bbrc.2006.09.069. Epub 2006 Sep 22.
PPARgamma agonists inhibit liver fibrosis, but the mechanisms involved are uncertain. We hypothesized that PPARgamma agonists inhibit transforming growth factor (TGF)beta1-activation of TGFbeta receptor (TGFbetaR)-1 signaling in quiescent stellate cells, thereby abrogating Smad3-dependent induction of extracellular matrix (ECM) genes, such as PAI-1 and collagen-1alphaI. To test this, human HSC were cultured to induce a quiescent phenotype, characterized by lipid accumulation and PPARgamma expression and transcriptional activity. These adipocytic HSC were then treated with TGFbeta1+/-a TGFbetaR-1 kinase inhibitor (SB431542) or a PPARgamma agonist (GW7845). TGFbeta1 caused dose- and time-dependent increases in Smad3 phosphorylation, followed by induction of collagen and PAI-1 expression. Like the TGFbetaR-1 kinase inhibitor, the PPARgamma agonist caused dose-dependent inhibition of all of these responses without effecting HSC proliferation or viability. Thus, the anti-fibrotic actions of PPARgamma agonists reflect their ability to inhibit TGFbeta1-TGFbetaR1 signaling that initiates ECM gene expression in quiescent HSC.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可抑制肝纤维化，但其作用机制尚不清楚。我们推测，PPARγ激动剂可抑制静止星状细胞中转化生长因子（TGF）β1对TGFβ受体（TGFβR）-1信号的激活，从而消除Smad3依赖的细胞外基质（ECM）基因（如纤溶酶原激活物抑制剂-1（PAI-1）和Ⅰ型胶原α1）的诱导。为验证这一推测，我们培养人肝星状细胞（HSC）以诱导出以脂质蓄积、PPARγ表达及转录活性为特征的静止表型。然后用TGFβ1±TGFβR-1激酶抑制剂（SB431542）或PPARγ激动剂（GW7845）处理这些脂肪细胞样HSC。TGFβ1可引起Smad3磷酸化呈剂量和时间依赖性增加，随后诱导胶原和PAI-1表达。与TGFβR-1激酶抑制剂一样，PPARγ激动剂可引起所有这些反应的剂量依赖性抑制，而不影响HSC增殖或活力。因此，PPARγ激动剂的抗纤维化作用反映了它们抑制TGFβ1-TGFβR1信号传导的能力，该信号传导可启动静止HSC中ECM基因的表达。
