Circadian rhythms and alcohol in the BMAL1 knockout rat - PROJECT SUMMARY
Liver disease is the number one cause of death from long-term heavy alcohol drinking in the United States. While
dose and duration of alcohol consumption are well-accepted risk factors for disease, it is clear that the etiology
of alcohol-related liver disease (ALD) is highly complex, involving many still unknown genetic, metabolic, and
environmental factors. This complexity also likely explains why there are so few effective therapies for treating
ALD. Therefore, a major unanswered question for the alcohol field is – what additional environmental factors,
metabolic impairments, and/or molecular disturbances are required for liver pathology to occur in the alcohol
consumer? A vital temporal integrator of environmental stimuli, metabolism, and cellular transcriptional control
is the circadian system. At the cellular level, 24-h circadian rhythms are driven by a transcriptional-translational
feedback loop system. This molecular clock mechanism involves activation of core clock genes and many
downstream clock-output genes by the transcriptional activators BMAL1 and CLOCK. This molecular clock
mechanism ensures that specific cellular and biological processes occur at the correct time of day. Accumulating
evidence shows that circadian rhythm disruption worsens tissue function and injury in animals and humans
consuming alcohol. Despite these new findings, the mechanistic understanding of how this occurs is very limited.
This current proposal addresses a critical target of alcohol toxicity – the mitochondrion. Even though multiple
studies have shown that alcohol severely impairs mitochondrial function, there have not been rigorous studies
examining the impact of circadian disruption on temporal control of hepatic mitochondrial function in the alcohol
consumer. We hypothesize that circadian disruption worsens alcohol-related impairments in hepatic
mitochondrial bioenergetic function and increases tissue injury. To test this hypothesis, we will use an exciting
new animal model, the Bmal1 knockout rat – the first rat model of a global clock gene knockout developed with
CRISPR/Cas9 genome editing technology. In Aim 1, we will determine the role of Bmal1 in the temporal control
of 24-h physiologic, metabolic, and molecular rhythms in alcohol-fed rats. In Aim 2, we will determine the role
Bmal1 in alcohol-related mitochondrial bioenergetic dysfunction and liver injury. Successful completion of these
studies will provide novel information regarding the interaction of the circadian system and alcohol on tissue and
mitochondrial function and pathology. The knowledge gained from this work also has the ability to influence
multiple scientific fields and facilitate development of novel chronotherapy-based approaches for treating patients
suffering from ALD and other related liver diseases.