The circadian clock and liver function in health and disease

Abstract

Each day, all organisms are subjected to changes in light intensity because of the Earth's rotation around its own axis. To anticipate this geo-physical variability, and to appropriately respond biochemically, most species, including mammals, have evolved an approximate 24-hour endogenous timing mechanism known as the circadian clock (CC). The 'clock' is self-sustained, cell autonomous and present in every cell type. At the core of the clock resides the CC-oscillator, an exquisitely crafted transcriptional-translational feedback system. Remarkably, components of the CC-oscillator not only maintain daily rhythmicity of their own synthesis, but also generate temporal variability in the expression levels of numerous target genes through transcriptional, post-transcriptional and post-translational mechanisms, thus, ensuring proper chronological coordination in the functioning of cells, tissues and organs, including the liver. Indeed, a variety of physiologically critical hepatic functions and cellular processes are CC-controlled. Thus, it is not surprising that modern lifestyle factors (e.g. travel and jet lag, night and rotating shift work), which force 'circadian misalignment', have emerged as major contributors to global health problems including obesity, non-alcoholic fatty liver disease and steatohepatitis. Herein, we provide an overview of the CC-dependent pathways which play critical roles in mediating several hepatic functions under physiological conditions, and whose deregulation is implicated in chronic liver diseases including non-alcoholic steatohepatitis and alcohol-related liver disease.

Rotating night shift work and non-alcoholic fatty liver disease among steelworkers in China: a cross-sectional survey

“…The following mechanisms may explain the association between rotating night shift work and NAFLD. As the core organ of human metabolism, the liver’s metabolic homoeostasis is regulated by the circadian clock 33. Bile acid dysregulation due to chronic circadian disruption can lead to an imbalance of nutrient use and storage 34.…”

Melatonin and circadian rhythms in liver diseases: Functional roles and potential therapies

“…This liver‐specific rhythm was dependent on light‐dark cycle, indicating that the liver may have independent circadian rhythms and functions . Since circadian rhythms regulate various physiological events throughout the body, the association of disrupted circadian rhythms with human disorders including liver diseases has been suggested …”

“…5 Since circadian rhythms regulate various physiological events throughout the body, the association of disrupted circadian rhythms with human disorders including liver diseases has been suggested. 7,8 Melatonin (N-acetyl-5-methoxytryptamine) is a hormone associated with circadian rhythms especially in the dark phase. Melatonin synthesis is facilitated at night and inhibited by light at daytime detected by retinas.…”

Insufficient nocturnal sleep was associated with a higher risk of fibrosis in patients with diabetes with metabolic associated fatty liver disease

“…The disruption of the circadian clock is detrimental to liver functions. 32 Our study revealed that in the case of dysregulated metabolic functions, with multiple influencing factors, sleep duration was still independently related to the progress of fatty liver disease, which highlighted the importance of sleep in regulating liver metabolism and homeostasis of the metabolic environment.…”