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Cellular senescence drives age-dependent hepatic steatosis

Ogrodnik, Mikolaj; Miwa, Satomi; Tchkonia, Tamar; Tiniakos, Dina; Wilson, Caroline L.; Lahat, Albert; Day, Christoper P.; Burt, Alastair; Palmer, Allyson; Anstee, Quentin M.; Grellscheid, Sushma Nagaraja; Hoeijmakers, Jan HJ.; Barnhoorn, Sander; Mann, Derek A.; Bird, Thomas G.; Vermeij, Wilbert P.; Kirkland, James L.; Passos, João F.; von Zglinicki, Thomas; Jurk, Diana

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Authors

Mikolaj Ogrodnik

Satomi Miwa

Tamar Tchkonia

Dina Tiniakos

Caroline L. Wilson

Albert Lahat

Christoper P. Day

Alastair Burt

Allyson Palmer

Quentin M. Anstee

Jan HJ. Hoeijmakers

Sander Barnhoorn

Derek A. Mann

Thomas G. Bird

Wilbert P. Vermeij

James L. Kirkland

João F. Passos

Thomas von Zglinicki

Diana Jurk



Abstract

The incidence of non-alcoholic fatty liver disease (NAFLD) increases with age. Cellular senescence refers to a state of irreversible cell-cycle arrest combined with the secretion of proinflammatory cytokines and mitochondrial dysfunction. Senescent cells contribute to age-related tissue degeneration. Here we show that the accumulation of senescent cells promotes hepatic fat accumulation and steatosis. We report a close correlation between hepatic fat accumulation and markers of hepatocyte senescence. The elimination of senescent cells by suicide gene-meditated ablation of p16Ink4a-expressing senescent cells in INK-ATTAC mice or by treatment with a combination of the senolytic drugs dasatinib and quercetin (D+Q) reduces overall hepatic steatosis. Conversely, inducing hepatocyte senescence promotes fat accumulation in vitro and in vivo. Mechanistically, we show that mitochondria in senescent cells lose the ability to metabolize fatty acids efficiently. Our study demonstrates that cellular senescence drives hepatic steatosis and elimination of senescent cells may be a novel therapeutic strategy to reduce steatosis.

Citation

Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., …Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nature Communications, 8, https://doi.org/10.1038/ncomms15691

Journal Article Type Article
Acceptance Date Apr 20, 2017
Online Publication Date Jun 13, 2017
Publication Date Jun 13, 2017
Deposit Date Jul 5, 2017
Publicly Available Date Mar 29, 2024
Journal Nature Communications
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 8
DOI https://doi.org/10.1038/ncomms15691

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/





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