Ogrodnik, Mikolaj and Miwa, Satomi and Tchkonia, Tamar and Tiniakos, Dina and Wilson, Caroline L. and Lahat, Albert and Day, Christoper P. and Burt, Alastair and Palmer, Allyson and Anstee, Quentin M. and Grellscheid, Sushma Nagaraja and Hoeijmakers, Jan H J. and Barnhoorn, Sander and Mann, Derek A. and Bird, Thomas G. and Vermeij, Wilbert P. and Kirkland, James L. and Passos, João F. and von Zglinicki, Thomas and Jurk, Diana (2017) 'Cellular senescence drives age-dependent hepatic steatosis.', Nature communications., 8 . p. 15691.
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.
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|Publisher Web site:||https://doi.org/10.1038/ncomms15691|
|Publisher 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/|
|Date accepted:||20 April 2017|
|Date deposited:||05 July 2017|
|Date of first online publication:||13 June 2017|
|Date first made open access:||05 July 2017|
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