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

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: Jul 5, 2017
• Journal: Nature Communications
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 8
• DOI: https://doi.org/10.1038/ncomms15691
• Public URL: https://durham-repository.worktribe.com/output/1353973