以色列魏茨曼科学研究所Gad Asher研究组发现，肝脏BMAL1和HIF1α调控时间依赖的缺氧反应并预防肝肺综合症。相关论文于2024年8月5日在线发表于国际学术期刊《细胞—代谢》。

研究人员报道了肝脏Bmal1和Hif1α在小鼠缺氧的昼夜节律反应中的作用。研究发现，大多数缺氧的转录反应依赖于Bmal1或Hif1α，且其作用具有昼夜决定性。研究人员进一步表明，缺氧诱导因子（HIF）1α在缺氧下的积累是时间依赖性且受Bmal1调控的。意外的是，缺乏肝脏Bmal1和Hif1α的小鼠在缺氧暴露下表现为低氧血症和昼夜依赖性的高死亡率。

这些小鼠显示出轻度的肝脏功能障碍，伴有由于细胞外信号调节激酶（ERK）激活、内皮型一氧化氮合酶和肺部一氧化氮积累导致的肺部血管舒张，提示可能存在肝肺综合症。该研究表明，肝脏BMAL1和HIF1α是缺氧反应的关键时间依赖性调控因子，并为肝肺综合症的发病机制提供了分子见解。

据悉，缺氧的转录反应具有时间依赖性，但其分子机制和生理意义尚不清楚。

附：英文原文

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

Author: Vaishnavi Dandavate, Nityanand Bolshette, Rachel Van Drunen, Gal Manella, Hanna Bueno-Levy, Mirie Zerbib, Ippei Kawano, Marina Golik, Yaarit Adamovich, Gad Asher

Issue&Volume: 2024-08-05

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

DOI: 10.1016/j.cmet.2024.07.003

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00274-2