Ethanol-stimulated differentiated functions of human or mouse hepatic stellate cells are mediated by connective tissue growth factor.
Ethanol-stimulated differentiated functions of human or mouse hepatic stellate cells are mediated by connective tissue growth factor.
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DOI：
10.1016/j.jhep.2010.11.025
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发表时间：
2011-08
影响因子：
25.7
通讯作者：
Brigstock DR
中科院分区：
文献类型：
--
作者：
Chen L;Charrier AL;Leask A;French SW;Brigstock DR
结缔组织生长因子（CTGF）的表达与肝纤维化的病理生理密切相关。在这项研究中，CTGF的生产和行动进行了研究，在乙醇处理的小鼠原代肝星状细胞（HSC）或人LX-2细胞。用乙醇或乙醛处理HSC后，用实时荧光定量PCR检测CTGF、转化生长因子-β 1（TGF-β1）、α-平滑肌肌动蛋白（α-SMA）和胶原α1（I）mRNA的表达。通过免疫沉淀或ELISA评估CTGF蛋白产生。使用CTGF启动子报告构建体研究乙醇刺激的CTGF转录。使用针对TGF-β 1或CTGF的小干扰RNA（siRNA）测定乙醇诱导的CTGF、α-SMA或胶原α1（I）的TGF-β 1或CTGF依赖性。在人脂肪性肝炎中，CTGF由假定活化的HSC产生。在培养的人或小鼠HSC中，CTGF、α-SMA和/或胶原蛋白的产生通过乙醇处理增加，乙醛模拟了这种作用，并被4-甲基吡唑（4-MP）或N-乙酰半胱氨酸（NAC）阻断。CTGF启动子活性被乙醇或TGF-β1以持续的方式刺激。CTGF启动子中Smad位点或基础控制元件（BCE-1）的突变导致乙醇刺激的CTGF启动子活性降低5倍。TGF-β1 siRNA或CTGF siRNA可显著降低LX-2细胞中CTGF、α-SMA或I型胶原的mRNA或蛋白水平。在小鼠HSC中，CTGF siRNA显著减弱TGF-β1或乙醇刺激的CTGF、α-SMA或胶原I。HSC中乙醇诱导的α-SMA或胶原α1（I）通过TGF-β依赖性CTGF产生介导，突出了靶向CTGF在酒精性肝病中的潜在治疗益处。
Connective tissue growth factor (CTGF) expression is intimately associated with hepatic fibrotic pathophysiology. In this study, CTGF production and action was investigated in ethanol-treated mouse primary hepatic stellate cells (HSC) or human LX-2 cells. CTGF, transforming growth factor-beta1 (TGF-β1), alpha-smooth muscle actin (α-SMA) or collagen α1(I) mRNA were quantified by real-time PCR after treatment of HSC with ethanol or acetaldehyde. CTGF protein production was assessed by immunoprecipitation or ELISA. Ethanol-stimulated CTGF transcription was investigated using CTGF promoter reporter constructs. The TGF-β1- or CTGF-dependency of ethanol-induced CTGF, α-SMA or collagen α1(I) was determined using small interfering RNA (siRNA) to TGF-β1 or CTGF. In human steatohepatitis, CTGF was produced by presumptive activated HSC. In cultured human or mouse HSC, production of CTGF, α-SMA and/or collagen was increased by ethanol treatment, an effect mimicked by acetaldehyde and blocked by 4-methylpyrazole (4-MP) or N-acetylcysteine (NAC). CTGF promoter activity was stimulated in a sustained fashion by ethanol or TGF-β1. Mutation of the Smad site or basal control element (BCE-1) in the CTGF promoter caused a 5-fold reduction in ethanol-stimulated CTGF promoter activity. Administration of TGF-β1 siRNA or CTGF siRNA significantly decreased ethanol- or acetaldehyde-stimulated mRNA or protein levels of CTGF, α-SMA or collagen I in LX-2 cells. In mouse HSC, TGF-β1- or ethanol-stimulated CTGF, α-SMA or collagen I were significantly attenuated by CTGF siRNA. Ethanol-induced α-SMA or collagen α1(I) in HSC are mediated via TGF-β-dependent CTGF production, highlighting potential therapeutic benefits of targeting CTGF in alcoholic liver disease.
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影响因子：
4.1
作者：
Leask, Andrew;Chen, Shaoqiong;Brigstock, David R.
通讯作者：
Brigstock, David R.
影响因子：
4.8
作者：
Leask, A;Holmes, A;Abraham, DJ
通讯作者：
Abraham, DJ
影响因子：
24.5
作者：
Xu, L;Hui, AY;Eng, FJ
通讯作者：
Eng, FJ
影响因子：
5.3
作者：
Huang G;Brigstock DR
通讯作者：
Brigstock DR
影响因子：
4.1
作者：
Brigstock, David R.
通讯作者：
Brigstock, David R.