# Circadian and mitochondrial dysfunction in alcohol-related liver disease

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2024 · $457,851

## Abstract

PROJECT SUMMARY
Alcohol-related liver disease (ALD) is the number one cause of death from long-term and excessive alcohol use
in the United States. One early and primary target of alcohol hepatotoxicity is the mitochondrion. Chronic alcohol
consumption severely compromises liver mitochondrial bioenergetic function; however, the specific molecular
mechanisms responsible for mitochondrial damage are not well understood. We also do not know the full
contribution of mitochondrial dysfunction in pathobiology of ALD. Accumulating evidence supports the concept
that an intrinsic biological mechanism known as the molecular circadian clock regulates how organs respond to
external environmental factors, as well as internal physiological stimuli and abnormal pathologic stresses. There
is a growing body of evidence that circadian rhythms are disrupted by chronic alcohol use, which likely contribute
to disease as genetic mutation or deletion of clock genes increase metabolic dysfunction and liver pathology in
alcohol models. Regarding this scientific premise, we discovered that chronic alcohol significantly deceases liver
clock amplitude and disrupts the timing of the liver clock. Alcohol-fed mice with liver-specific deletion of Bmal1
exhibit impaired glucose and glycogen metabolism rhythms, a dysregulated hepatic triglyceride lipidome, and a
greater liver disease pathology score compared to control genotype mice fed an alcohol diet. We also have
exciting new preliminary data showing chronic alcohol significantly dampens and disrupts rhythmicity of critical
hepatic mitochondrial bioenergetic functions, including activity of cytochrome c oxidase, the rate-limiting enzyme
of mitochondrial respiration. Building on these exciting new observations, we offer a new paradigm where loss
in circadian control of mitochondrial bioenergetic function during chronic alcohol consumption plays a key causal
role in the pathogenesis of ALD. We will test this hypothesis through three Specific Aims. In Aim 1, we will
establish that chronic alcohol consumption disrupts 24-h rhythms in hepatic mitochondrial bioenergetic function.
In Aim 2, we will define the roles of hepatocyte BMAL1 and E4BP4 in alcohol-induced mitochondrial bioenergetic
dysfunction and liver injury. In Aim 3, we will test if reinstating liver clock activity during alcohol use prevents
mitochondrial dysfunction and liver injury. These results will provide the first insights into the relationship between
the circadian system and alcohol on mitochondrial bioenergetics and organ damage. Project findings will have
direct translational impact by advancing pre-clinical scientific knowledge required for stimulating drug discovery
in the areas of mitochondrial and chronobiology based therapeutics for treating patients afflicted with ALD and
other serious liver diseases.

## Key facts

- **NIH application ID:** 10839944
- **Project number:** 5R01AA029072-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** SHANNON MARIE BAILEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $457,851
- **Award type:** 5
- **Project period:** 2023-05-10 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10839944

## Citation

> US National Institutes of Health, RePORTER application 10839944, Circadian and mitochondrial dysfunction in alcohol-related liver disease (5R01AA029072-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10839944. Licensed CC0.

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