Hepatic BMAL1 and HIF1a regulate a time-dependent hypoxic response and their absence leads to Hepatopulmonary Syndrome II

The transcriptional response to hypoxia is temporally regulated yet the molecular underpinnings and physiological implications are unknown. We examined herein the roles of hepatic Bmal1 and Hif1a in the circadian response to hypoxia in mice. We found that the majority of the transcriptional response to hypoxia is dependent on Bmal1 or Hif1a, through shared and distinct roles that are daytime determined. We further show that HIF1a accumulation upon hypoxia is temporally regulated and Bmal1-dependent. Unexpectedly, mice lacking both hepatic Bmal1 and Hif1a 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 ERK activation, endothelial nitric oxide synthase and nitric oxide accumulation in lungs, suggestive of hepatopulmonary syndrome. Our findings indicate that hepatic BMAL1 and HIF1a are key time-dependent regulators of the response to hypoxia and provide molecular insight on the pathophysiology of hepatopulmonary syndrome.