Περίληψη:
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. © The Author(s) 2017.
Συγγραφείς:
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.
Λέξεις-κλειδιά:
cyclin dependent kinase inhibitor 2A; dasatinib; fatty acid; quercetin; Cdkn2a protein, mouse; cyclin dependent kinase inhibitor 2A, age; biochemistry; cells and cell components; disease incidence; drug; fat; gene expression; mitochondrion; physiological response; rodent; secretion; senescence, animal cell; animal experiment; animal model; Article; cell aging; centromere; controlled study; fatty acid metabolism; fatty liver; in vitro study; in vivo study; lipid storage; liver biopsy; liver cell; male; mitochondrion; mouse; nonhuman; senescence; suicide gene; telomere; animal; apoptosis; C57BL mouse; cell aging; cell culture; chemistry; cytology; drug effect; fatty liver; fibroblast; inflammation; liver; metabolism; nonalcoholic fatty liver; pathology; transgenic mouse, Mus, Animals; Apoptosis; Cells, Cultured; Cellular Senescence; Cyclin-Dependent Kinase Inhibitor p16; Dasatinib; Fatty Liver; Fibroblasts; Hepatocytes; Inflammation; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria; Non-alcoholic Fatty Liver Disease; Quercetin
