Abstract
A wide variety of liver functions are regulated daily by the liver circadian clock and via systemic circadian control by other organs and cells within the gastrointestinal tract as well as the microbiome and immune cells. Disruption of the circadian system, as occurs during jetlag, shift work or an unhealthy lifestyle, is implicated in several liver-related pathologies, ranging from metabolic diseases such as obesity, type 2 diabetes mellitus and nonalcoholic fatty liver disease to liver malignancies such as hepatocellular carcinoma. In this Review, we cover the molecular, cellular and organismal aspects of various liver pathologies from a circadian viewpoint, and in particular how circadian dysregulation has a role in the development and progression of these diseases. Finally, we discuss therapeutic and lifestyle interventions that carry health benefits through support of a functional circadian clock that acts in synchrony with the environment.
Key points
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Liver physiology and metabolism exhibit daily rhythmicity under the governance of the circadian clock.
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Circadian clocks are implicated in metabolic diseases, such as obesity and diabetes, through hepatic and hepatic-associated mechanisms.
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Clock components have a role in the pathophysiology of a wide variety of liver pathologies, from nonalcoholic fatty liver disease to hepatocellular carcinoma.
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The microbiome and the immune system are emerging clock-controlled regulators of metabolic health.
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Circadian-based medicine in the form of time-of-day nutritional and pharmacological interventions carries health benefits.
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Acknowledgements
The authors are grateful to all members of the Asher and Reinke labs for their comments on the manuscript. G.A. is supported by a grant from the European Research Council (ERC-2017 CIRCOMMUNICATION 770869), Abisch Frenkel Foundation for the Promotion of Life Sciences, Adelis Foundation, and Susan and Michael Stern.
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G.A. and H.R. made a substantial contribution to the discussion of content, wrote the article, and reviewed and edited the manuscript before submission. N.B. and H.I. researched data for the article, made a substantial contribution to the discussion of content, and wrote the article.
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Bolshette, N., Ibrahim, H., Reinke, H. et al. Circadian regulation of liver function: from molecular mechanisms to disease pathophysiology. Nat Rev Gastroenterol Hepatol 20, 695–707 (2023). https://doi.org/10.1038/s41575-023-00792-1
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DOI: https://doi.org/10.1038/s41575-023-00792-1
