Melatonin alleviates alcoholic liver disease via EGFR-BRG1-TERT axis regulation.
Melatonin alleviates alcoholic liver disease via EGFR-BRG1-TERT axis regulation.
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褪黑素通过 EGFR–BRG1–TERT 轴调节减轻酒精性肝病
DOI：
10.1016/j.apsb.2022.06.015
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发表时间：
2023-01
影响因子：
14.5
通讯作者：
Xiao, Jia
中科院分区：
文献类型：
--
作者：
Che, Zhaodi;Song, Yali;Xu, Chengfang;Li, Wei;Dong, Zhiyong;Wang, Cunchuan;Ren, Yixing;So, Kwok-Fai;Tipoe, George L.;Wang, Fei;Xiao, Jia
长期饮酒会导致肝脏脂肪变性、细胞死亡和炎症。褪黑激素（MLT）被报道可以减轻酒精性肝病（ALD）引起的损伤。然而，其在肝细胞中的直接调节靶点尚未完全了解。在本研究中，使用基于细胞的筛选模型和慢性乙醇喂养的小鼠ALD模型来测试MLT的保护机制。在细胞和动物模型中，MLT可改善乙醇诱导的肝细胞损伤（最佳剂量分别为10 μmol/L和5 mg/kg），包括降低肝脏脂肪变性、细胞死亡和炎症。在AML-12细胞中进行的RNA-seq分析和功能丧失研究表明，端粒酶逆转录酶（TERT）是MLT的关键下游效应子。生物物理分析发现，肝细胞表面的表皮生长因子受体（EGFR）是MLT的直接结合和调节靶点。在ALD小鼠模型中，肝脏特异性敲低Tert或Egfr损害了MLT介导的肝脏保护作用，部分通过调节核brahma相关基因1（BRG 1）。健康小鼠长期给药（90天）未引起明显不良反应。总之，MLT是缓解ALD的有效和安全的药物。其在肝细胞中的直接调节靶点是EGFR和下游BRG 1-TERT轴。MLT可用作酗酒者的补充剂。褪黑激素通过直接结合和调节肝细胞表面EGFR来抑制乙醇诱导的肝脂肪变性、细胞死亡和炎症，从而抑制核BRG 1表达并增强下游TERT活性。
Chronic alcohol consumption causes liver steatosis, cell death, and inflammation. Melatonin (MLT) is reported to alleviate alcoholic liver disease (ALD)-induced injury. However, its direct regulating targets in hepatocytes are not fully understood. In the current study, a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT. MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models (optimal doses of 10 μmol/L and 5 mg/kg, respectively), including lowered liver steatosis, cell death, and inflammation. RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase (TERT) was a key downstream effector of MLT. Biophysical assay found that epidermal growth factor receptor (EGFR) on the hepatocyte surface was a direct binding and regulating target of MLT. Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection, partly through the regulation of nuclear brahma-related gene-1 (BRG1). Long-term administration (90 days) of MLT in healthy mice did not cause evident adverse effect. In conclusion, MLT is an efficacious and safe agent for ALD alleviation. Its direct regulating target in hepatocytes is EGFR and downstream BRG1–TERT axis. MLT might be used as a complimentary agent for alcoholics. Melatonin alleviates ethanol-induced liver steatosis, cell death, and inflammation through a direct binding and regulation of hepatocyte surface EGFR, to inhibit nuclear BRG1 expression and enhance downstream TERT activity.
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