Excessive alcohol consumption remains a leading cause of preventable death in the United States. Alcoholic liver disease (ALD) is a major cause of morbidity and mortality from heavy alcohol drinking and is the most prevalent cause of liver disease-related death. Despite increased understanding of the many cellular and molecular events occurring in ALD, the causal mechanisms remain elusive, especially with regards to the factors responsible for disease progression and severity. To advance mechanistic understanding of this serious liver disease, the current proposal will investigate the importance of circadian clock disruption and `time-of-day' as critical risk factors for ALD. These views stem from the growing recognition that circadian clock disruption is linked to numerous pathologies and diseases. One essential function of the molecular circadian clock is to provide a selective advantage of anticipation, allowing for rapid and temporally appropriate adaptation to metabolic stress, immune challenges, and environmental insults. When these processes fail, disease ensues. We propose that perturbation of circadian clocks underlie many of the metabolic and inflammatory events contributing to alcohol-induced liver injury. As such, we will determine the role of the hepatocyte clock and the monocyte clock in alcohol-induced liver injury. In support of this concept, we have found that the circadian clock is significantly altered in livers of chronic alcohol-fed mice, genetic disruption of the liver clock increases levels of hepatic inflammatory mediators, and alcohol-induced liver injury and steatosis are elevated in mice with a disrupted liver clock. Furthermore, studies show that disruptions in normal time-of-day patterns in alcohol drinking increases risk for ALD and binge alcohol drinking is now recognized to be harmful to health. Collectively, these observations have led us to hypothesize that circadian clock disruption exacerbates alcohol-induced liver injury and inflammation. Similarly, we propose that the magnitude of alcohol toxicity is dependent on the time of day of alcohol ingestion. We will test these hypotheses through two specific aims.
In Aim 1, we will mechanistically show the critical role of cell autonomous clocks in chronic alcohol- induced liver injury by using two genetic mouse models, the hepatocyte-specific BMAL1 knockout mouse and the monocyte (myeloid cell)-specific BMAL1 knockout mouse.
In Aim 2, we will use the `chronic + binge' alcohol model and determine the `window' or time of day that the liver is most sensitive to alcohol binge toxicity. Successful completion of this project will reveal the importance of cell-specific circadian clocks in alcohol-mediated tissue injury and inflammation and show that `time-of-day' is a significant risk factor for liver injury from binge alcohol drinking. Our long-term goal is that the scientific knowledge gained from these pre- clinical animal studies will lead to future translational investigations using various chronobiology-based therapeutic approaches for treatment of ALD and other related liver diseases.
Excessive alcohol use remains a top ten cause of preventable death in the United States; sadly we still do not fully understand the mechanisms responsible for alcohol toxicity and there are few effective treatments. The studies in this research proposal are important as they will address the exciting new hypothesis that circadian clock disruption and the time of day at which alcohol is consumed significantly influence alcohol-induced liver injury. Importantly, the new scientific information gained from this research will help scientists and medical professionals better understand the causes of liver disease and lead to the discovery of new treatments for patients suffering from liver diseases associated with many conditions including diabetes, obesity, hepatitis C, and alcoholism.
