Emerging role of circadian clock disruption in alcohol-induced liver disease

Abstract

The detrimental health effects of excessive alcohol consumption are well documented. Alcohol-induced liver disease (ALD) is the leading cause of death from chronic alcohol use. As with many diseases, the etiology of ALD is influenced by how the liver responds to other secondary insults. The molecular circadian clock is an intrinsic cellular timing system that helps organisms adapt and synchronize metabolism to changes in their environment. The clock also influences how tissues respond to toxic, environmental, and metabolic stressors, like alcohol. Consistent with the essential role for clocks in maintaining health, genetic and environmental disruption of the circadian clock contributes to disease. While a large amount of rich literature is available showing that alcohol disrupts circadian-driven behaviors and that circadian clock disruption increases alcohol drinking and preference, very little is known about the role circadian clocks play in alcohol-induced tissue injuries. In this review, recent studies examining the effect alcohol has on the circadian clock in peripheral tissues (liver and intestine) and the impact circadian clock disruption has on development of ALD are presented. This review also highlights some of the rhythmic metabolic processes in the liver that are disrupted by alcohol and potential mechanisms through which alcohol disrupts the liver clock. Improved understanding of the mechanistic links between the circadian clock and alcohol will hopefully lead to the development of new therapeutic approaches for treating ALD and other alcohol-related organ pathologies.

Keywords: alcohol; circadian clock; desynchrony; liver; steatosis.

Fig. 1.

The molecular circadian clock system and hepatic clock gene rhythms. A: the molecular circadian clock mechanism comprises transcriptional-translational feedback loops that control 24-h rhythms in clock genes and numerous other clock-controlled genes. At the core of the clock mechanism is the BMAL1-CLOCK heterodimer that activates transcription of multiple clock genes including components that comprise the negative feedback loops (PER, CRY, and REV-ERB), the positive feedback loop (ROR), and the transcription factors that regulate Bmal1 expression (ROR and REV-ERB). These feedback loops also regulate transcription of numerous non-clock metabolic genes. B: diurnal oscillations of Bmal1, Per2, and Dbp mRNA levels in livers from wild-type C57BL/6J male mice fed a normal chow diet. Livers were collected every 4 h [Zeitgeber time (ZT) 0 = lights on, ZT 12 = lights off]. Data significantly fit to a cosine function and represent the means ± SE for n = 4–6 mice per time point.

Fig. 2.

A hypothetical model for alcohol-mediated disruption of the liver circadian clock and liver injury. It is hypothesized that alcohol-mediated alterations in the circadian clock system contribute, in part, to the development of alcohol-induced steatosis and liver injury. There are many ways that alcohol might disrupt clock activity in the liver; herein, only a few hypothetical mechanisms are proposed. First, it is likely that alcohol-mediated alterations to intestinal clocks increases gut permeability, releasing LPS into the portal circulation with the ensuing alterations in hepatic inflammation and metabolism altering the liver clock. Second, alcohol-induced changes in the hepatic redox and energy state are also proposed to disrupt clock function. While the precise molecular mechanisms responsible for these alcohol-mediated effects on the clock are unknown, it is proposed that alterations in cellular redox may disrupt diurnal rhythms in BMAL1-CLOCK DNA binding along with the activities of the NAD⁺-dependent enzymes SIRT1 and PARP1, which modulate the phase and amplitude of circadian rhythms. Similarly, alcohol-mediated alterations in ATP-dependent kinase activities, e.g., AMPK, may negatively affect clock protein functions and timing. These alterations to the clock would, in turn, perturb clock-controlled rhythms in various downstream metabolic and/or signaling processes implicated in alcohol-induced liver injury, including, but not limited to, pathways in glycogen, lipid, cholesterol, and mitochondrial metabolism. Select targets are listed in the figure from cited papers. An alcohol-induced loss in flexible day-night rhythms in hepatic energy metabolism is predicted to cause a state of metabolic “inflexibility” in liver, thus hindering the liver’s ability to respond to changing energy demands throughout the day and perform critical cellular functions, including the repair of alcohol-induced tissue damage. It is also likely that alterations in these energy metabolism pathways might even “feedback” and further contribute to alcohol-mediated clock disruption thereby intensifying tissue injury.