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

Autor:	Dandavate V; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel., Bolshette N; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel., Van Drunen R; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel., Manella G; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel., Bueno-Levy H; Department of the Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel., Zerbib M; Department of the Veterinary Resources, Weizmann Institute of Science, 7610001 Rehovot, Israel., Kawano I; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel., Golik M; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel., Adamovich Y; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel., Asher G; Department of Biomolecular Sciences, Weizmann Institute of Science, 7610001 Rehovot, Israel. Electronic address: gad.asher@weizmann.ac.il.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2024 Sep 03; Vol. 36 (9), pp. 2038-2053.e5. Date of Electronic Publication: 2024 Aug 05.
DOI:	10.1016/j.cmet.2024.07.003
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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