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  • Review Article
  • Published:

Circadian rhythms of liver physiology and disease: experimental and clinical evidence

Nature Reviews Gastroenterology & Hepatology volume 13, pages 217–226 (2016)Cite this article

Subjects

Key Points

  • The circadian clock system is a feedback loop of core clock genes and proteins, with post-transcriptional and post-translational regulation, in each cell in nearly every peripheral tissue

  • Nuclear receptors and transcription factors are important for regulating circadian rhythms and rhythmic energy metabolism

  • The liver clock tightly regulates the pharmacokinetics of xenobiotics through each phase, including absorption and uptake, distribution, metabolism, and elimination and clearance

  • Disorganization of circadian clocks in the liver exacerbates liver diseases, including fatty liver, cholestasis, hepatitis, cirrhosis and liver cancer, and these diseases can in turn disrupt the circadian clock system

  • Chrononutrition, the control of circadian clocks by nutrition, is a powerful tool and might be a basic component of life in both humans and animal models

Abstract

The circadian clock system consists of a central clock located in the suprachiasmatic nucleus in the hypothalamus and peripheral clocks in peripheral tissues. Peripheral clocks in the liver have fundamental roles in maintaining liver homeostasis, including the regulation of energy metabolism and the expression of enzymes controlling the absorption and metabolism of xenobiotics. Over the past two decades, research has investigated the molecular mechanisms linking circadian clock genes with the regulation of hepatic physiological functions, using global clock-gene-knockout mice, or mice with liver-specific knockout of clock genes or clock-controlled genes. Clock dysfunction accelerates the development of liver diseases such as fatty liver diseases, cirrhosis, hepatitis and liver cancer, and these disorders also disrupt clock function. Food is an important regulator of circadian clocks in peripheral tissues. Thus, controlling the timing of food consumption and food composition, a concept known as chrononutrition, is one area of active research to aid recovery from many physiological dysfunctions. In this Review, we focus on the molecular mechanisms of hepatic circadian gene regulation and the relationships between hepatic circadian clock systems and liver physiology and disease. We concentrate on experimental data obtained from cell or mice and rat models and discuss how these findings translate into clinical research, and we highlight the latest developments in chrononutritional studies.

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Figure 1: Overview of the circadian clock system in mammals.
Figure 2: Core molecular clock machinery.
Figure 3: Chronopharmacokinetics of xenobiotics.
Figure 4: Circadian machinery in liver disease.
Figure 5: Chrononutrition in the liver.

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Acknowledgements

We thank C. Feillet (Université Nice Sophia Antipolis, France) for providing many helpful suggestions during the writing of this manuscript. The authors are partially supported by the Council for Science, Technology, and Innovation (CSTI); the Cross-ministerial Strategic Innovation Promotion Program (SIP); and Technologies for Creating Next-generation Agriculture, Forestry, and Fisheries (funding agency: Bio-oriented Technology Research Advancement Institution), NARO (National Agriculture and Food Research Organization), and a Grant-in-Aid for Scientific Research (S) (26220201) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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Authors and Affiliations

  1. Waseda Institute for Advanced Study, Waseda University, Shinjuku-ku, 162–8480, Tokyo, Japan

    Yu Tahara

  2. Laboratory of Physiology and Pharmacology, School of Advanced Science and Engineering, Waseda University, Wakamatsu-cho 2–2, Shinjuku-ku, 162–8480, Tokyo, Japan

    Shigenobu Shibata

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  1. Yu Tahara
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Y.T. and S.S researched data for the article, made substantial contributions to the discussion of content, wrote the article, and reviewed and edited the manuscript before submission.

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Correspondence to Shigenobu Shibata.

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Tahara, Y., Shibata, S. Circadian rhythms of liver physiology and disease: experimental and clinical evidence. Nat Rev Gastroenterol Hepatol 13, 217–226 (2016). https://doi.org/10.1038/nrgastro.2016.8

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