肝脏 BMAL1 和 HIF1α 可调节时间依赖性缺氧反应并预防肝肺样综合征

IF 27.7 1区 生物学 Q1 CELL BIOLOGY
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引用次数: 0

摘要

对低氧的转录反应是受时间调控的,但其分子基础和生理意义尚不清楚。我们研究了肝脏 Bmal1 和 Hif1α 在小鼠对低氧的昼夜节律反应中的作用。我们发现,大部分对低氧的转录反应都依赖于 Bmal1 或 Hif1α,它们既有共同的作用,也有不同的作用,这些作用都是在白天确定的。我们进一步发现,缺氧诱导因子(HIF)1α在缺氧时的积累是受时间调控的,并且依赖于Bmal1。出乎意料的是,同时缺乏肝脏 Bmal1 和 Hif1α 的小鼠会出现低氧血症,并在缺氧暴露时表现出死亡率升高,且升高程度与时间有关。这些小鼠表现出轻度肝功能障碍,肺部血管扩张可能是由于细胞外信号调节激酶(ERK)激活、内皮一氧化氮合酶和肺部一氧化氮蓄积所致,提示肝肺综合征。我们的研究结果表明,肝脏 BMAL1 和 HIF1α 是缺氧反应的关键时间依赖性调节因子,可为肝肺综合征的病理生理学提供分子见解。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome

Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome

The transcriptional response to hypoxia is temporally regulated, yet the molecular underpinnings and physiological implications are unknown. We examined the roles of hepatic Bmal1 and Hif1α in the circadian response to hypoxia in mice. We found that the majority of the transcriptional response to hypoxia is dependent on either Bmal1 or Hif1α, through shared and distinct roles that are daytime determined. We further show that hypoxia-inducible factor (HIF)1α accumulation upon hypoxia is temporally regulated and Bmal1 dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1α are hypoxemic and exhibit increased mortality upon hypoxic exposure in a daytime-dependent manner. These mice display mild liver dysfunction with pulmonary vasodilation likely due to extracellular signaling regulated kinase (ERK) activation, endothelial nitric oxide synthase, and nitric oxide accumulation in lungs, suggestive of hepatopulmonary syndrome. Our findings indicate that hepatic BMAL1 and HIF1α are key time-dependent regulators of the hypoxic response and can provide molecular insights into the pathophysiology of hepatopulmonary syndrome.

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来源期刊
Cell metabolism
Cell metabolism 生物-内分泌学与代谢
CiteScore
48.60
自引率
1.40%
发文量
173
审稿时长
2.5 months
期刊介绍: Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.
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