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CO-Induced TTP Activation Alleviates Cellular Senescence and Age-Dependent Hepatic Steatosis via Downregulation of PAI-1
Aging can increase the risk of various hepatic diseases, especially non-alcoholic fatty liver disease (NAFLD). Although the mechanisms underlying the pathogenesis of age-related disorders such as NAFLD remain incompletely understood, recent studies have implicated the accumulation of senescent cells...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
JKL International LLC
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10017156/ https://www.ncbi.nlm.nih.gov/pubmed/37008056 http://dx.doi.org/10.14336/AD.2023.0120 |
Sumario: | Aging can increase the risk of various hepatic diseases, especially non-alcoholic fatty liver disease (NAFLD). Although the mechanisms underlying the pathogenesis of age-related disorders such as NAFLD remain incompletely understood, recent studies have implicated the accumulation of senescent cells as a contributing factor. Here, we show that tristetraprolin (TTP) deficiency accelerates NAFLD during aging by enhancing the senescence-associated secretory phenotype (SASP) as well as several hallmarks of senescence. The sequestration of plasminogen activator inhibitor (PAI)-1, a mediator of cellular senescence, in stress granules, (SGs) inhibits cellular senescence. In our previous report, we have shown that carbon monoxide (CO), a small gaseous mediator, can induce the assembly of SGs via an integrated stress response. Here, we show that CO treatment promotes the assembly of SGs which can sequester PAI-1, resulting in the inhibition of etoposide (ETO)-induced cellular senescence. Notably, CO-induced TTP activation enhances PAI-1 degradation, leading to protection against ETO-induced cellular senescence. CO-dependent Sirt1 activation promotes the inclusion of TTP into SGs, leading to decreased PAI-1 levels. Therefore, our findings highlight the importance of TTP as a therapeutic target in age-related NAFLD and offer a potential new strategy to reduce the detrimental effects of senescent cells in hepatic disorders. |
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