在人类小岛模型中,酸碳化合物受体和缺氧诱导因子1α通路之间的交叉连接
Noa Gang1,2, Kyle A van Allen1, William G Willmore1
1Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, ON, Canada.
Islets
|July 18, 2025
概括
像TCDD这样的环境污染物会激活胰腺小岛中的基碳化合物受体 (AHR). 这项研究研究了AHR和缺氧诱导因子1α (HIF1α) 的交叉,发现缺氧干扰了小岛的AHR激活.
科学领域:
- 内分泌学 在内分泌学.
- 环境健康 环境健康
- 分子生物学分子生物学
背景情况:
- 持久性有机污染物,如2,3,7,8-四二子二氧化 (TCDD),激活基碳化合物受体 (AHR).
- 已知AHR与各种细胞类型中的缺氧诱导因子1α (HIF1α) 相互作用.
- 在胰腺小岛中AHR和HIF1α之间的交叉,对于代谢调节至关重要,此前没有被探索,尽管小岛对缺氧敏感.
研究的目的:
- 研究胰腺小岛细胞中氧诱导因子1α (HIF1α) 途径与烯碳化合物受体 (AHR) 之间的交叉.
- 为了确定TCDD诱导的AHR激活是否会在低氧条件下干扰HIF1α通路的反应.
- 评估对小岛细胞功能和生存的潜在有害影响.
主要方法:
- 人体供体小岛和干细胞衍生小岛 (SC-小岛) 在正常或缺氧 (1% O2) 条件下用TCDD (10 nM) 治疗.
- 测量了AHR (例如,CYP1A1) 和HIF1α (例如,HMOX1) 的下游目标的基因表达.
- 葡萄糖刺激胰岛素分泌 (GSIS) 在人类小岛上进行了评估.
主要成果:
- 在SC小岛中,缺氧抑制了TCDD诱导的CYP1A1表达,表明了AHR-HIF1α交叉.
- 在6个捐赠者中的2个人类小岛中观察到类似的CYP1A1抑制.
- 在两个小岛模型中,低氧抑制了G6PC2表达,并在人类小岛中损害了GSIS,但单独的TCDD并不影响GSIS.
结论:
- 在SC岛屿中观察到一致的AHR-HIF1α交叉,在初级人类岛屿中观察到可变的交叉.
- 低氧干扰了TCDD诱导的AHR通路激活,但AHR激活没有干扰HIF1α通路.
- 同时暴露于环境污染物和低氧导致胰腺小岛的分子交叉声,这对小岛的功能和生存有影响.
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