Circadian clock disruption aggravates alcohol liver disease in an acute mouse model

ABSTRACT

Circadian rhythms are important for organisms to adapt to the environment and maintain homeostasis. Disruptions of circadian rhythms contribute to the occurrence, progression, and exacerbation of diseases, such as cancer, psychiatric disorders, and metabolic disorders. Alcohol-induced liver disease (ALD) is one of the most prevalent liver diseases. Disruptions of the circadian clock enhance the ALD symptoms using chronic mice models or genetic manipulated mice. However, chronic models are time consuming and clock gene deletions interfere with metabolisms. Here, we report that constant light (LL) condition significantly disrupted the circadian clock in an acute ALD model, resulting in aggravated ALD phenotypes in wild type mice. Comparative transcriptome analysis revealed that the alcohol feeding affected the circadian pathway, as well as metabolic pathways. The acute alcohol feeding plus the LL condition further interfered with metabolic pathways and dysregulated canonical circadian gene expressions. These findings support the idea that disrupting the circadian clock could provide an improved ALD mouse model for further applications, such as facilitating identification of potential therapeutic targets for the prevention and treatment of ALD.

Abbreviations: ALD, alcohol-induced liver disease; LD, 12 h light _ 12 h dark; LL, constant light; HF, high-fat liquid control diet; ETH, ethanol-containing diet; NIAAA, National Institute on Alcohol Abuse and Alcoholism; TTFLs, transcription-translation feedback loops; FDA, US Foods and Drug Administration; NAFLD, non-alcoholic fatty liver disease; RER, respiratory exchange rate; DEGs, differentially expressed genes; H&E, haematoxylin and eosin; ALT, alanine transaminase; AST, aspartate transaminase; TG, triglycerides.

KEYWORDS:

• Alcohol-induced liver disease
• circadian clock
• disrupted circadian clock
• metabolic rhythm
• mouse model

Acknowledgements

We are grateful to the staff for providing technical support with using the facility of the Institute of Health Sciences at Anhui University.

Author contributions

J.G., H.G., and X.Q. conceived and designed the research; J.G., X.S., L.S., performed the research J.G., Q.Z., S.J., and Y.Z. analyzed the data; J.G. and X.Q. wrote the manuscript; Y.Z., H.G., and X.Q. edited the manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/07420528.2022.2132865

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was financially supported by the grant from the National Natural Science Foundation of China (32071158 to X.Q.), and by the grants from Anhui Provincial Natural Science Foundation (2008085MC68 to X.Q.), and partially supported by the National Natural Science Foundation of China (31970103 to H.G.).