Molecular circadian clocks and alcohol-induced liver injury

在美国，过度饮酒仍然是可预防死亡的主要原因。酒精 肝病（ALD）是大量饮酒导致发病和死亡的主要原因， 肝病相关死亡的普遍原因。尽管对许多细胞和 分子事件发生在ALD，因果机制仍然难以捉摸，特别是关于 导致疾病进展和严重程度的因素。为了推进对这个问题的机械理解， 严重的肝脏疾病，目前的建议将调查生物钟中断的重要性， “一天中的时间”是ALD的关键风险因素。这些观点源于人们越来越认识到生物钟 破坏与许多病理和疾病有关。分子生物钟的一个基本功能 时钟是提供一个选择性的优势，预期，允许快速和时间适当的 适应代谢应激、免疫挑战和环境损伤。当这些过程失败时， 疾病发作我们认为，生物钟的扰动是许多代谢和 导致酒精性肝损伤的炎症事件。因此，我们将确定 肝细胞时钟和单核细胞时钟在酒精性肝损伤中的作用。为了支持这一概念，我们 发现慢性酒精喂养的小鼠肝脏的生物钟发生了显着改变， 肝脏时钟增加肝脏炎症介质的水平，以及酒精诱导的肝损伤， 脂肪变性在肝脏时钟被破坏的小鼠中升高。此外，研究表明， 饮酒的时间模式增加了ALD的风险，现在认为酗酒 对健康有害。总的来说，这些观察使我们假设生物钟的破坏 加重酒精引起的肝损伤和炎症。同样，我们认为酒精的含量 毒性取决于摄入酒精的时间。我们将通过两个具体的实验来验证这些假设。 目标。在目标1中，我们将机械地显示细胞自主时钟在慢性酒精中的关键作用。 通过使用两种遗传小鼠模型，肝细胞特异性BMAL 1敲除小鼠和 单核细胞（骨髓细胞）特异性BMAL 1敲除小鼠。在目标2中，我们将使用“慢性+暴食” 酒精模型，并确定“窗口”或一天中的时间，肝脏是最敏感的酒精狂欢 毒性该项目的成功完成将揭示细胞特异性昼夜节律钟在细胞内的重要性。 酒精介导的组织损伤和炎症，并表明“一天中的时间”是肝脏的一个重要风险因素 酗酒造成的伤害。我们的长期目标是，从这些预- 临床动物研究将导致未来的翻译研究， 用于治疗ALD和其他相关肝病的治疗方法。

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.