Cellular senescence drives age-dependent hepatic steatosis

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

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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.

Original languageEnglish (US)
Article number15691
JournalNature communications
Volume8
DOIs
StatePublished - Jun 13 2017

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ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Ogrodnik, M., Miwa, S., Tchkonia, T., Tiniakos, D., Wilson, C. L., Lahat, A., Day, C. P., Burt, A., Palmer, A., Anstee, Q. M., Grellscheid, S. N., Hoeijmakers, J. H. J., Barnhoorn, S., Mann, D. A., Bird, T. G., Vermeij, W. P., Kirkland, J. L., Passos, J. F., Von Zglinicki, T., & Jurk, D. (2017). Cellular senescence drives age-dependent hepatic steatosis. Nature communications, 8, [15691]. https://doi.org/10.1038/ncomms15691