Circadian and mitochondrial dysfunction in alcohol-related liver disease

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.