Universität zu Köln

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:	Creators Email ORCID ORCID Put Code Ogrodnik, Mikolaj UNSPECIFIED orcid.org/0000-0003-3137-2037 UNSPECIFIED Miwa, Satomi UNSPECIFIED orcid.org/0000-0002-1239-1198 UNSPECIFIED Tchkonia, Tamar UNSPECIFIED orcid.org/0000-0003-4623-7145 UNSPECIFIED Tiniakos, Dina UNSPECIFIED UNSPECIFIED UNSPECIFIED Wilson, Caroline L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lahat, Albert UNSPECIFIED orcid.org/0000-0001-5648-3011 UNSPECIFIED Day, Christopher P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Burt, Alastair UNSPECIFIED UNSPECIFIED UNSPECIFIED Palmer, Allyson UNSPECIFIED orcid.org/0000-0001-7505-3455 UNSPECIFIED Anstee, Quentin M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Grellscheid, Sushma Nagaraja UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoeijmakers, Jan H. J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Barnhoorn, Sander UNSPECIFIED UNSPECIFIED UNSPECIFIED Mann, Derek A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bird, Thomas G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vermeij, Wilbert P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirkland, James L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Passos, Joao F. UNSPECIFIED UNSPECIFIED UNSPECIFIED von Zglinicki, Thomas UNSPECIFIED orcid.org/0000-0002-5939-0248 UNSPECIFIED Jurk, Diana UNSPECIFIED orcid.org/0000-0003-4486-0857 UNSPECIFIED
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:	Keywords Language DNA-DAMAGE RESPONSE; HEPATOCYTE SENESCENCE; OXIDATIVE STRESS; SCORING SYSTEM; LIVER-CANCER; CELLS; MITOCHONDRIA; DYSFUNCTION; PROGRESSION; TISSUE Multiple languages Multidisciplinary Sciences Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22779