Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent
Early response of α2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-β independent
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DOI：
10.1002/hep.20798
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发表时间：
2005-08-01
期刊：
影响因子：
13.5
通讯作者：
Rojkind, M
中科院分区：
文献类型：
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作者：
Svegliati-Baroni, G;Inagaki, Y;Rojkind, M
乙醛具有致纤维化作用，可诱导肝星状细胞I型胶原基因表达。这些乙酰丙酮依赖性事件中的一些是由H2 O2介导的，因此在氧化应激和胶原上调之间建立了直接联系。我们定位于α 2（I）胶原（COL 1A 2）启动子的-378至-183区域，在人肝星状细胞（HHSC）中起作用的乙酰丙酮酸去应答元件（AcRE），并研究乙醛刺激和调节其转录活性的分子机制。由于ACRE与先前描述的转化生长因子β（TGF-β）1-反应元件共定位，并且乙醛和该细胞因子均通过H2 O2诱导其作用，因此我们研究了乙醛的所有纤维化作用是否均由该细胞因子介导。在这里，我们发现乙酰丙酮酸诱导的HHSC中COL 1A（2）上调识别两个不同但重叠的早期和晚期阶段，分别持续1至6小时和6至24小时。我们提出了几条证据表明，早期乙酰丙酮酸介导的事件是独立的TGF-β 1。这些包括COL 1A 2和TGF-β 1 mRNA表达的显著时程差异以及TGF-β 1中和抗体不能抑制乙酰丙酮依赖性胶原基因转录和Smad 3磷酸化。我们还表明，虽然乙酰丙酮依赖性胶原蛋白的上调是PI 3 K依赖性的，但TGF-β 1的上调是PI 3 K独立的。总之，参与COL 1A 2上调的乙酰丙酮依赖性机制与TGF-β 1的机制相似，但不相同。我们认为，早期乙酰丙酮依赖性事件诱导TGF-β 1的晚期表达，并建立一个H2 O2依赖性自分泌回路，可能维持和放大这种酒精代谢产物的纤维化反应。
Acetaldehyde is fibrogenic and induces the expression of type I collagen genes in hepatic stellate cells. Some of these acetaldehyde-dependent events are mediated by H2O2 and thus establish a direct connection between oxidative stress and collagen upregulation. We localized to the -378 to -183 region of the alpha 2(I) collagen (COL1A2) promoter an acetaldehyde-responsive element (AcRE) functional in human hepatic stellate cells (HHSCs) and investigated molecular mechanisms whereby acetaldehyde stimulates and modulates its transcriptional activity. Because the ACRE co-localized with a previously described transforming growth factor beta (TGF-beta)1-responsive element, and both acetaldehyde and this cytokine induce their effects through H2O2, we investigated whether all fibrogenic actions of acetaldehyde were mediated by this cytokine. Here we show that acetaldehyde-induced COL1A(2) upregulation in HHSCs recognizes two distinct but overlapping early and late stages that last from 1 to 6 hours and from 6 to 24 hours, respectively. We present several lines of evidence to show that early acetaldehyde-mediated events are independent of TGF-beta 1. These include significant time-course differences in the expression of COL1A2 and TGF-beta 1 mRNAs and inability of neutralizing antibodies to TGF-/31 to inhibit acetaldehyde-dependent collagen gene transcription and Smad 3 phosphorylation. We also show that although acetaldehyde-dependent upregulation of collagen was PI3K dependent, that of TGF-beta 1 was PI3K independent In conclusion, acetaldehyde-dependent mechanisms involved in COL1A2 upregulation are similar, but not identical, to those of TGF-beta 1. We suggest that early acetaldehyde-dependent events induce the late expression of TGF-beta 1 and create an H2O2-dependent autocrine loop that may sustain and amplify the fibrogenic response of this alcohol metabolite.