Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome (Dandavate et al, 2024)

Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome
Vaishnavi Dandavate 1 , Nityanand Bolshette 1 , Rachel Van Drunen 1 , Gal Manella 1 , Hanna Bueno-Levy 2 , Mirie Zerbib 2 , Ippei Kawano 1 , Marina Golik 1 , Yaarit Adamovich 1 , Gad Asher 3
Affiliations

• PMID: 39106859
• DOI: 10.1016/j.cmet.2024.07.003

Abstract
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.

 

I'm posting this one because I've never seen hypoxia responses linked to circadian issues before. But they are, the paper claims, linked.

There's a mystery in mecfs which perhaps this could shed some light on, and that is that people report feeling better at different times of day. The most common story is people who start to feel a bit better in the evening. I've never had any insight on that, but the above paper hints that vasodilatory processes could be involved.

The paper has another really interesting point which is that the interaction between hypoxia and circadian rhythms is a two-way street. Sleep apnea, for example, ruins circadian rhythms, the paper says. I wonder if poor oxygenation could, via this pathway, help account for poor sleep and disturbed circadian rhythms in me/cfs?