Why the early hours of the day can be particularly dangerous to our health

Researchers at the Weizmann Institute of Science in Israel have found a possible explanation for this phenomenon.

In a study published in the journal Cell Metabolism, scientists found that a key component of our circadian rhythms - the internal 24-hour molecular clock running in each cell - also regulates the body's response to oxygen deprivation. This component, which varies throughout the day, may influence the timing of diseases related to the body's oxygen cycle.

The role of oxygen and the internal clock

As living beings, we are extremely dependent on our ability to sense and respond to oxygen deficiency. The 2019 Nobel Prize in Physiology or Medicine was awarded for the discovery of hypoxia-inducible factor 1-alpha (HIF-1α), a key protein that determines how cells respond to oxygen deficiency. Under normal oxygen levels, HIF-1α is unstable and rapidly degrades, but under oxygen deficiency it stabilises and activates genes that help adapt to hypoxia.

However, HIF-1α is not the only important element. Professor Usher's team, including doctoral student Vaishnavi Dandavate and Dr Nityananda Bolshette, found that the BMAL1 protein, a key component of our circadian clock, also plays a key role in the response to oxygen deprivation. It is required for the stabilisation and activation of HIF-1α.

Moreover, BMAL1 not only acts together with HIF-1α, but also independently triggers the body's mechanisms to fight oxygen deficiency. This may explain why the body's response to hypoxia and related diseases varies throughout the day.

Daytime and nighttime squirrels

Previously, Asher's lab discovered that liver tissue responds differently to oxygen deprivation at different times of day. To further this understanding, they created three groups of genetically modified mice whose livers lacked either HIF-1α, BMAL1, or both proteins.

When oxygen levels were reduced, it turned out that without BMAL1, the HIF-1α protein did not accumulate as it normally does. This showed that both proteins, individually and together, are responsible for the genetic response to hypoxia.

Professor Asher said: 'The mechanism we discovered is probably the primary way in which mammals cope with oxygen deprivation. Our findings have helped us understand that the circadian clock not only responds to hypoxia, but also actively triggers mechanisms to cope with it.

Surprisingly, mice without both proteins had low survival rates in oxygen deprivation, especially during darkness. This indicates that the combination of HIF-1α and BMAL1 plays an important role depending on the time of day.

New discoveries and future treatments

Further studies showed that the cause of death in these mice was not the liver, but a decrease in the lungs' ability to absorb oxygen. This is similar to hepatopulmonary syndrome in people with liver disease, where the dilation of blood vessels in the lungs reduces oxygen saturation.

The scientists found these mice had an increased production of nitric oxide in the lungs, which caused blood vessels to dilate and reduced the efficiency of oxygen supply.

Prof Asher added: We don't yet know how liver damage affects lung function, but our findings point to a group of proteins that may be the link between the two. If these proteins are also involved in this process in humans, they could be a target for future therapies.

Source: Vaishnavi Dandavate et al, Hepatic BMAL1 and HIF1α regulate a time-dependent hypoxic response and prevent hepatopulmonary-like syndrome, Cell Metabolism (2024). DOI: 10.1016/j.cmet.2024.07.003

Journal information: Cell Metabolism