期刊
NATURE COMMUNICATIONS
卷 8, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms15691
关键词
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资金
- Newcastle University Faculty of Medical Sciences Fellowship
- National Institute for Health Research
- David Phillips BBSRC fellowship [BB/H022384/1]
- BBSRC [BB/K017314/1, BB/ C008200/1, BB/I020748/1]
- NIH [R37 AG013925]
- Connor Group
- Noaber Foundation
- Centre for Ageing Vitality [MR/M501700, MK/K001949/1, MRC G0700890]
- Wellcome Trust [WT107492]
- NUIA
- Newcastle Biomedical Research Centre
- National Institute of Health (NIH)/National Institute of Ageing (NIA) [PO1 AG017242]
- European Research Council
- KWO Dutch Cancer Society [5030]
- Royal Academy of Arts and Sciences of the Netherlands
- [SFB628]
- Biotechnology and Biological Sciences Research Council [1369828, BB/I020748/1, BB/K017314/1, BB/H022384/1, BB/F010966/1] Funding Source: researchfish
- Cancer Research UK [22311, 24009] Funding Source: researchfish
- Medical Research Council [MR/L016354/1, MR/K001949/1] Funding Source: researchfish
- Wellcome Trust [107492/Z/15/Z] Funding Source: researchfish
- Wellcome Trust [107492/Z/15/Z] Funding Source: Wellcome Trust
- BBSRC [BB/I020748/1, BB/K017314/1, BB/F010966/1, BB/H022384/1] Funding Source: UKRI
- MRC [MR/L016354/1, MR/K001949/1] Funding Source: UKRI
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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