The College of Life Science and Bioengineering, Beijing Jiaotong University, No.3 Shangyuancun Road, Beijing, 100044, People's Republic of China.
The Chinese Academy of Inspection and Quarantine, Beijing, People's Republic of China.
J Mol Med (Berl). 2019 Oct;97(10):1399-1412. doi: 10.1007/s00109-019-01808-7. Epub 2019 Jul 18.
S100A4, a member of the S100 calcium-binding protein family, has been identified in a subpopulation of liver macrophages and promotes liver fibrosis via hepatic stellate cell activation. However, the specific role of S100A4 in alcoholic liver disease (ALD) has not been well investigated. Here, S100A4 knockout (S100A4) mice were used in a chronic-binge ethanol model for studying the role of S100A4 and its related molecular mechanism in ALD. S100A4 expression was increased in ethanol-induced liver tissues of wild-type (WT) mice. Macrophage-derived S100A4 promoted liver inflammation but suppressed lipid accumulation under the ethanol feeding condition. S100A4 deficiency promoted ethanol-induced liver injury and hepatic fat accumulation. Further mechanistic studies found that S100A4 inhibited liver fat accumulation mainly by activating the STAT3 pathway and downregulating lipogenic gene expression, especially that of SREBP-1c. In AML-12 cells, a STAT3 inhibitor abolished STAT3 levels and decreased the expression of SREBP1c. Furthermore, the administration of a neutralizing S100A4 antibody to WT mice significantly promoted ethanol-induced liver injury and fatty accumulation. Thus, S100A4 may represent a potential candidate target for the prevention and treatment of ethanol-induced fatty liver. In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c. KEY MESSAGES: In this study, we discovered the special role of S100A4 in alcoholic liver disease. S100A4 deficiency attenuated ethanol-induced hepatitis and promoted hepatic fat accumulation in ethanol-induced liver tissues. Further mechanistic studies have found that S100A4 promotes early alcoholic hepatitis mainly by activating the STAT3 pathway and its downstream proinflammatory gene expression. Interestingly, activation of the STAT3 pathway downregulates lipogenic gene expression, especially SREBP-1c.
S100A4 是 S100 钙结合蛋白家族的成员，在肝巨噬细胞亚群中被鉴定出来，并通过激活肝星状细胞促进肝纤维化。然而，S100A4 在酒精性肝病 (ALD) 中的具体作用尚未得到充分研究。在这里，我们使用 S100A4 敲除 (S100A4) 小鼠在慢性 binge 乙醇模型中研究 S100A4 及其相关分子机制在 ALD 中的作用。在野生型 (WT) 小鼠的乙醇诱导的肝组织中，S100A4 的表达增加。在乙醇喂养条件下，巨噬细胞来源的 S100A4 促进肝脏炎症，但抑制脂质积累。S100A4 缺乏促进乙醇诱导的肝损伤和肝脂肪堆积。进一步的机制研究发现，S100A4 主要通过激活 STAT3 通路和下调脂肪生成基因表达，特别是 SREBP-1c 的表达，抑制肝脂肪积累。在 AML-12 细胞中，STAT3 抑制剂消除了 STAT3 水平并降低了 SREBP1c 的表达。此外，向 WT 小鼠施用中和 S100A4 抗体可显著促进乙醇诱导的肝损伤和脂肪堆积。因此，S100A4 可能是预防和治疗乙醇诱导的脂肪肝的潜在候选靶点。在这项研究中，我们发现了 S100A4 在酒精性肝病中的特殊作用。S100A4 缺乏可减轻乙醇诱导的肝炎，并促进乙醇诱导的肝组织中肝脂肪堆积。进一步的机制研究发现，S100A4 主要通过激活 STAT3 通路及其下游促炎基因表达来促进早期酒精性肝炎。有趣的是，STAT3 通路的激活下调了脂肪生成基因的表达，特别是 SREBP-1c。关键信息：在这项研究中，我们发现了 S100A4 在酒精性肝病中的特殊作用。S100A4 缺乏可减轻乙醇诱导的肝炎，并促进乙醇诱导的肝组织中肝脂肪堆积。进一步的机制研究发现，S100A4 主要通过激活 STAT3 通路及其下游促炎基因表达来促进早期酒精性肝炎。有趣的是，STAT3 通路的激活下调了脂肪生成基因的表达，特别是 SREBP-1c。
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