胰岛素决定转化生长因子β对肝细胞核因子4α转录的影响 肝细胞中的核因子4α转录
Rilu Feng1, Chenhao Tong1, Tao Lin1
1Section Molecular Hepatology, Department of Medicine II, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
The American journal of pathology
|October 11, 2023
概括
转化生长因子-β (TGF-β) 通过抑制CCAAT/增强剂结合蛋白α (C/EBPα) 转录来抑制肝细胞核因子4α (HNF4α). 肝脏胰岛素敏感性对于在炎症期间维持HNF4α表达至关重要.
科学领域:
- 肝病学 肝病学是一种肝病学.
- 分子生物学分子生物学
- 炎症研究 炎症研究
背景情况:
- 肝细胞核因子4α (HNF4α) 表达的丧失在末期肝病中很常见,导致肝功能受损和死亡率增加.
- 像转化生长因子-β (TGF-β) 这样的炎症性细胞因子与HNF4α下调有关,但确切的机制尚不清楚.
研究的目的:
- 阐明TGF-β抑制肝细胞中HNF4α表达的分子机制.
- 研究胰岛素敏感性在调节炎症条件下的HNF4α表达中的作用.
主要方法:
- 研究了TGF-β对HNF4α促进体活性和调控蛋白的招募的影响,使用了体外测试.
- 在患者肝脏活检中分析了-SMAD2,C/EBPα和HNF4α的表达.
- 研究了胰岛素对SMAD2/3与C/EBPα促进体结合的影响,并评估了葡萄糖转运体2型 (GLUT2) 表达作为胰岛素耐药性的指标.
主要成果:
- TGF-β通过招募CREB结合蛋白/p300到HNF4α促进剂间接促进HNF4α表达,这对于C/EBPα结合至关重要.
- 由TGF-β激活的SMAD2/3,抑制了C/EBPα转录,导致C/EBPα耗尽,随后失去HNF4α表达.
- 患者数据证实了-SMAD2,C/EBPα和HNF4α表达之间的关联.
- 胰岛素消除了SMAD2/3对C/EBPα转录的抑制作用,C/EBPα缺乏与减少GLUT2表达相关,表明胰岛素耐药性.
结论:
- TGF-β诱导的炎症通过SMAD2/3介导的C/EBPα转录的抑制抑制HNF4α的表达.
- 肝脏胰岛素敏感性是维持炎症期间HNF4α表达的关键因素,由胰岛素对SMAD2/3介导的C/EBPα抑制的保护作用证明了这一点.
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