Ogrodnik, Mikolaj ORCID: 0000-0003-3137-2037, Miwa, Satomi ORCID: 0000-0002-1239-1198, Tchkonia, Tamar ORCID: 0000-0003-4623-7145, Tiniakos, Dina, Wilson, Caroline L., Lahat, Albert ORCID: 0000-0001-5648-3011, Day, Christopher P., Burt, Alastair, Palmer, Allyson ORCID: 0000-0001-7505-3455, Anstee, Quentin M., Grellscheid, Sushma Nagaraja, Hoeijmakers, Jan H. J., Barnhoorn, Sander, Mann, Derek A., Bird, Thomas G., Vermeij, Wilbert P., Kirkland, James L., Passos, Joao F., von Zglinicki, Thomas ORCID: 0000-0002-5939-0248 and Jurk, Diana ORCID: 0000-0003-4486-0857 (2017). Cellular senescence drives age-dependent hepatic steatosis. Nat. Commun., 8. LONDON: NATURE PUBLISHING GROUP. ISSN 2041-1723

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Ogrodnik, MikolajUNSPECIFIEDorcid.org/0000-0003-3137-2037UNSPECIFIED
Miwa, SatomiUNSPECIFIEDorcid.org/0000-0002-1239-1198UNSPECIFIED
Tchkonia, TamarUNSPECIFIEDorcid.org/0000-0003-4623-7145UNSPECIFIED
Tiniakos, DinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilson, Caroline L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lahat, AlbertUNSPECIFIEDorcid.org/0000-0001-5648-3011UNSPECIFIED
Day, Christopher P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burt, AlastairUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palmer, AllysonUNSPECIFIEDorcid.org/0000-0001-7505-3455UNSPECIFIED
Anstee, Quentin M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grellscheid, Sushma NagarajaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoeijmakers, Jan H. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Barnhoorn, SanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mann, Derek A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bird, Thomas G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vermeij, Wilbert P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kirkland, James L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Passos, Joao F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Zglinicki, ThomasUNSPECIFIEDorcid.org/0000-0002-5939-0248UNSPECIFIED
Jurk, DianaUNSPECIFIEDorcid.org/0000-0003-4486-0857UNSPECIFIED
URN: urn:nbn:de:hbz:38-227798
DOI: 10.1038/ncomms15691
Journal or Publication Title: Nat. Commun.
Volume: 8
Date: 2017
Publisher: NATURE PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 2041-1723
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE RESPONSE; HEPATOCYTE SENESCENCE; OXIDATIVE STRESS; SCORING SYSTEM; LIVER-CANCER; CELLS; MITOCHONDRIA; DYSFUNCTION; PROGRESSION; TISSUEMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22779

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