FASN activity is important for the initial stages of the induction of senescence.,Cell Death & Disease

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FASN activity is important for the initial stages of the induction of senescence.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-04-08 , DOI: 10.1038/s41419-019-1550-0
Juan Fafián-Labora _{1,

2} , Paula Carpintero-Fernández _{1,

2} , Samuel James Davison Jordan _{1,

2} , Tamanna Shikh-Bahaei _{1,

2} , Sana Mohammad Abdullah _{1,

2} , Midusa Mahenthiran _{1,

2} , José Antonio Rodríguez-Navarro ₃ , Maria Victoria Niklison-Chirou ₂ , Ana O'Loghlen _{1,

2}

Affiliation

Senescent cells accumulate in several tissues during ageing and contribute to several pathological processes such as ageing and cancer. Senescence induction is a complex process not well defined yet and is characterized by a series of molecular changes acquired after an initial growth arrest. We found that fatty acid synthase (FASN) levels increase during the induction of senescence in mouse hepatic stellate cells and human primary fibroblasts. Importantly, we also observed a significant increase in FASN levels during ageing in mouse liver tissues. To probe the central role of FASN in senescence induction, we used a small-molecule inhibitor of FASN activity, C75. We found that C75 treatment prevented the induction of senescence in mouse and human senescent cells. Importantly, C75 also reduced the expression of the signature SASP factors interleukin 1α (IL-1α), IL-1β and IL-6, and suppressed the secretion of small extracellular vesicles. These findings were confirmed using a shRNA targeting FASN. In addition, we find that FASN inhibition induces metabolic changes in senescent cells. Our work underscores the importance of C75 as a pharmacological inhibitor for reducing the impact of senescent cell accumulation.

中文翻译：

FASN活性对于诱导衰老的初始阶段很重要。

衰老细胞在衰老过程中会积聚在多个组织中，并参与衰老和癌症等多种病理过程。衰老诱导是一个尚未明确定义的复杂过程，其特征是在最初的生长停滞后获得了一系列分子变化。我们发现，在小鼠肝星状细胞和人原代成纤维细胞衰老的诱导过程中，脂肪酸合酶（FASN）的水平增加。重要的是，我们还观察到小鼠肝组织衰老过程中FASN水平显着增加。为了探测FASN在衰老诱导中的核心作用，我们使用了FASN活性的小分子抑制剂C75。我们发现，C75处理可防止在小鼠和人类衰老细胞中诱导衰老。重要的，C75还降低了标志性SASP因子白介素1α（IL-1α），IL-1β和IL-6的表达，并抑制了小细胞外囊泡的分泌。使用针对FASN的shRNA证实了这些发现。此外，我们发现FASN抑制诱导衰老细胞的代谢变化。我们的工作强调了C75作为降低衰老细胞积累影响的药理抑制剂的重要性。

更新日期：2019-04-08

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