Abstract
Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.
Highlights
Excessive alcohol use remains a top ten cause of preventable death in the US [1]
Our laboratory has reported that depletion in hepatic glycogen levels is likely due to chronic alcohol-induced alterations in the time-of-day dependent rhythms of key components of hepatic glycogen metabolism [14]. These studies demonstrate that chronic alcohol consumption disrupts diurnal oscillations in liver metabolic genes that are likely under clock control and strongly supports the hypothesis that chronic alcohol consumption has a significant impact on liver metabolic processes that function in a circadian/diurnal fashion
The general thesis of this review article is that the function of the circadian clock and clock-regulated mechanisms are negatively impacted by alcohol consumption, resulting in cell dysfunction and tissue pathology
Summary
Excessive alcohol use remains a top ten cause of preventable death in the US [1]. Statistics show that alcohol use contributes to almost 90,000 deaths and over 2.5 million years of potential life lost for each year in the US from 2006–2010 [2,3]. Alcoholic liver disease (ALD) is a significant cause of morbidity and mortality from heavy and binge alcohol use. It is the number one cause of death from chronic alcohol consumption. While it has long been believed that the severity of ALD is dependent on the dose and duration of alcohol consumption, it has become clear that, like many other diseases, the pathology of ALD is complex and a product of multiple gene-environment-metabolic interactions This concept is highlighted by the observation that only 25% of heavy drinkers develop alcoholic steatohepatitis with less than 10%.
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