Cellular steatosis in ethanol oxidizing-HepG2 cells is partially controlled by the transcription factor, early growth response-1.
Cellular steatosis in ethanol oxidizing-HepG2 cells is partially controlled by the transcription factor, early growth response-1.
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DOI：
10.1016/j.biocel.2012.10.002
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发表时间：
2013-02
影响因子：
4
通讯作者：
Donohue, Terrence M., Jr.
中科院分区：
文献类型：
--
作者：
Thomes, Paul G.;Osna, Natalia A.;Davis, John S.;Donohue, Terrence M., Jr.
最近的研究表明，转录因子早期生长反应-1 （Egr-1）调节酒精性脂肪肝。然而，乙醇氧化控制Egr-1的机制尚不清楚。在这里，使用代谢乙醇的重组肝癌（HepG2; VL-17A）细胞，我们发现乙醇氧化和随后的乙醛生产的乙醇脱氢酶催化控制了Egr-1的表达。此外，Egr-1的诱导增强了其他脂肪变性相关基因的表达，导致甘油三酯积累。乙醇暴露增加了VL-17A细胞中Egr-1启动子活性、信使RNA和Egr-1蛋白水平。升高的Egr-1蛋白是通过乙醇诱导的蛋白酶体活性降低来维持的，从而稳定了Egr-1蛋白。Egr-1的诱导依赖于乙醇氧化，因为当乙醇氧化被阻断时，它就被阻止了。乙醇暴露仅在产生乙醛的表达乙醇脱氢酶的细胞中诱导Egr-1和甘油三酯积累。这种诱导在亲本非代谢的HepG2细胞或仅表达细胞色素P450 2E1的细胞中没有发生。然而，HepG2细胞直接暴露于乙醛诱导Egr-1蛋白和甘油三酯。Egr-1过表达会使甘油三酯水平升高，乙醇暴露会使甘油三酯水平升高。然而，这些甘油三酯水平并没有超过正常Egr-1表达的乙醇暴露细胞的水平。相反，通过siRNA敲低Egr-1只能部分阻断乙醇诱导的甘油三酯积累，并且不仅与Egr-1表达降低有关，还与SREBP1c和TNF-α mrna的衰减有关。双重下调Egr-1和SREBP-1c可消除乙醇引起的脂肪变性。总的来说，我们的发现为乙醇氧化Egr-1和细胞脂肪变性的时间调节提供了重要的新见解。
Recent studies have shown that the transcription factor early growth response-1 (Egr-1) regulates ethanol-induced fatty liver. However, the mechanism(s) through which ethanol oxidation controls Egr-1 is unknown. Here, using recombinant hepatoma (HepG2; VL-17A) cells that metabolize ethanol, we show that alcohol dehydrogenase catalysis of ethanol oxidation and subsequent acetaldehyde production controls Egr-1 expression. Further, the induction of Egr-1 enhances expression of other steatosis-related genes, resulting in triglyceride accumulation. Ethanol exposure increased Egr-1 promoter activity, messenger RNA and Egr-1 protein levels in VL-17A cells. Elevated Egr-1 protein was sustained by an ethanol-induced decrease in proteasome activity, thereby stabilizing the Egr-1 protein. Egr-1 induction depended on ethanol oxidation, as it was prevented when ethanol oxidation was blocked. Ethanol exposure induced Egr-1 and triglyceride accumulation only in alcohol dehydrogenase-expressing cells that produced acetaldehyde. Such induction did not occur in parental, non-metabolizing HepG2 cells or in cells that express only cytochrome P450 2E1. However, direct exposure of HepG2 cells to acetaldehyde induced both Egr-1 protein and triglycerides. Egr-1 over-expression elevated triglyceride levels, which were augmented by ethanol exposure. However, these triglyceride levels did not exceed those in ethanol-exposed cells that had normal Egr-1 expression. Conversely, Egr-1 knockdown by siRNA only partially blocked ethanol-induced triglyceride accumulation and was associated not only with lower Egr-1 expression but also attenuation of SREBP1c and TNF-α mRNAs. Double knockdown of both Egr-1 and SREBP-1c abolished ethanol-elicited steatosis. Collectively, our findings provide important new insights into the temporal regulation by ethanol oxidation of Egr-1 and cellular steatosis.
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影响因子：
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作者：
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通讯作者：
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作者：
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作者：
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