Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice
Early growth response-1 transcription factor is essential for ethanol-induced fatty liver injury in mice
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DOI：
10.1053/j.gastro.2005.02.065
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发表时间：
2005-06-01
期刊：
影响因子：
29.4
通讯作者：
Nagy, LE
中科院分区：
文献类型：
--
作者：
McMullen, MR;Pritchard, MT;Nagy, LE
背景和目标：早期生长反应-1（Egr-1）是一种立即早期基因/锌指转录因子，是脂多糖（LPS）刺激肿瘤坏死因子α（TNF-α）转录所必需的。由于慢性乙醇暴露使巨噬细胞对LPS刺激的TNF-α表达敏感，我们研究了Egr-1在慢性乙醇喂养后介导LPS刺激的TNF-α表达增加中的作用。此外，由于TNF-α有助于酒精性肝损伤，我们测试了Egr-1是野生型和Egr-1 -/-小鼠中乙醇诱导的脂肪肝损伤发展所必需的假设。方法：给野生型和BALB-1 -/-小鼠喂食含乙醇的饮食或成对喂食对照饮食6周。结果：喂食乙醇饲料的野生型小鼠出现以微泡和大泡脂质积聚为特征的肝脏脂肪变性。然而，在乙醇喂养后，α-1 -/-小鼠没有发生脂肪变性。在野生型小鼠中，乙醇喂养后血清中丙氨酸转移酶和TNF-α浓度增加，而非IFN-1 -/-小鼠。在野生型小鼠中，挑战与LPS增加Egr-1信使RNA（mRNA）和DNA结合活性在肝脏中，这种反应增强后，慢性乙醇喂养。与成对喂养的野生型小鼠相比，在乙醇喂养后，LPS攻击也在更大程度上增加了肝脏TNF-α mRNA和血清TNF-α。然而，慢性乙醇喂养并没有提高LPS刺激的TNF-α mRNA或血清TNF-α在TNF-1 -/-小鼠。结论：这些数据表明，Egr-1有助于增加慢性乙醇后LPS介导的TNF-α表达，Egr-1的缺乏可预防慢性乙醇诱导的脂肪肝，以及对LPS的敏感性增加。
Background & Aims: Early growth response-1 (Egr-1), an immediate early gene/zinc-finger transcription factor, is required for maximal stimulation of tumor necrosis factor alpha (TNF-alpha) transcription in response to lipopolysaccharide (LPS). Because chronic ethanol exposure sensitizes macrophages to LPS-stimulated TNF-alpha expression, we have investigated the role of Egr-1 in mediating increased LPS-stimulated TNF-alpha expression after chronic ethanol feeding. Furthermore, because TNF-alpha contributes to alcoholic liver injury, we tested the hypothesis that Egr-1 is required for the development of ethanol-induced fatty liver injury in wild type and egr-1 -/- mice. Methods: Wild-type and egr-1 -/- mice were fed ethanol-containing diets or pair-fed control diets for 6 weeks. Results: Wild-type mice fed the ethanol diet developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. However, egr-1 -/- mice did not develop steatosis after ethanol feeding. Alanine transferase and TNF-alpha concentrations in serum were increased after ethanol feeding in wildtype but not egr-1 -/- mice. In wild-type mice, challenge with LPS increased Egr-1 messenger RNA (mRNA) and DNA binding activity in liver; this response to LPS was enhanced after chronic ethanol feeding. LPS challenge also increased hepatic TNF-alpha mRNA and serum TNF-a to a greater extent after ethanol feeding compared with pair-fed wild-type mice. However, chronic ethanol feeding did not enhance LPS-stimulated TNF-a mRNA or serum TNF-a in egr-1 -/- mice. Conclusions: These data show that Egr-1 contributes to increased LPS-mediated TNF-alpha expression after chronic ethanol and that the absence of Egr-1 prevents chronic ethanol-induced fatty liver, as well as increased sensitivity to LPS.