| First Author | Dandavate V | Year | 2024 |
| Journal | Cell Metab | Volume | 36 |
| Issue | 9 | Pages | 2038-2053.e5 |
| PubMed ID | 39106859 | Mgi Jnum | J:361056 |
| Mgi Id | MGI:7714422 | Doi | 10.1016/j.cmet.2024.07.003 |
| Citation | Dandavate V, et al. (2024) Hepatic BMAL1 and HIF1alpha regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome. Cell Metab |
| abstractText | 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 Hif1alpha 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 Hif1alpha, through shared and distinct roles that are daytime determined. We further show that hypoxia-inducible factor (HIF)1alpha accumulation upon hypoxia is temporally regulated and Bmal1 dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1alpha 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 HIF1alpha are key time-dependent regulators of the hypoxic response and can provide molecular insights into the pathophysiology of hepatopulmonary syndrome. |
