β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4.
β-Hydroxybutyrate Prevents Vascular Senescence through hnRNP A1-Mediated Upregulation of Oct4.
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DOI：
10.1016/j.molcel.2018.07.036
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发表时间：
2018-09-20
期刊：
影响因子：
16
通讯作者：
Zou MH
中科院分区：
文献类型：
--
作者：
Han YM;Bedarida T;Ding Y;Somba BK;Lu Q;Wang Q;Song P;Zou MH
在禁食或热量限制期间，β-羟基丁酸（β-HB）升高被认为可以诱导抗衰老作用并缓解衰老相关的神经变性。然而，β-HB是否改变了血管细胞的衰老途径仍不清楚。在这里，我们报道了β-HB促进血管细胞静止，通过p53不依赖的机制显著抑制应激诱导的过早衰老和复制性衰老。此外，我们发现异质核核糖核蛋白A1 （hnRNP A1）是β-HB的直接结合靶点。β-HB结合hnRNP A1显著增强hnRNP A1与Oct - 4mrna的结合，稳定Oct - 4mrna和Oct4的表达。Oct4增加层粘胶蛋白B1，这是防止DNA损伤引起的衰老的关键因素。最后，在体内小鼠血管平滑肌和内皮细胞中，禁食和腹腔注射β-HB均上调Oct4和Lamin B1。我们得出结论，β-HB通过上调hnRNP a1诱导的oct4介导的Lamin B1通路，在血管细胞中发挥抗衰老作用。β-羟基丁酸通过诱导细胞静止来防止血管细胞衰老。β-羟基丁酸盐诱导的血管细胞静止依赖于Oct4的表达，Oct4通过与Oct4 mrna形成hnRNP A1复合物而上调。β-羟基丁酸诱导的Oct4表达与体内血管衰老的标志负相关。
β-hydroxybutyrate (β-HB) elevation during fasting or caloric restriction is believed to induce antiaging effects and alleviate aging-related neurodegeneration. However, whether β-HB alters the senescence pathway in vascular cells, remains unknown. Here we report that β-HB promotes vascular cell quiescence, which significantly inhibits both stress-induced premature senescence and replicative senescence through p53-independent mechanisms. Further, we identify heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) as a direct binding target of β-HB. β-HB binding to hnRNP A1 markedly enhances hnRNP A1 binding with Octamer-binding transcriptional factor (Oct) 4 mRNA, which stabilizes Oct 4 mRNA and Oct4 expression. Oct4 increases Lamin B1, a key factor against DNA damage-induced senescence. Finally, fasting and intraperitoneal injection of β-HB upregulate Oct4 and Lamin B1 in both vascular smooth muscle and endothelial cells in mice in vivo. We conclude that β-HB exerts anti-aging effects in vascular cells by upregulating an hnRNP A1-induced Oct4-mediated Lamin B1 pathway. β-hydroxybutyrate prevents vascular cell senescence via inducing cell quiescence. β-hydroxybutyrate-induced vascular cell quiescence is dependent on Oct4 expression, which is upregulated by forming hnRNP A1 complex with Oct4 mRNAs. β-hydroxybutyrate-induced Oct4 expression is negatively correlated with hallmarks of vascular senescence in vivo.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
DOI：
10.1038/nrg3473
发表时间：
2013-06
期刊：
Nature reviews. Genetics
影响因子：
--
作者：
通讯作者：
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影响因子：
--
作者：
Liu R;Liu H;Ha Y;Tilton RG;Zhang W
通讯作者：
Zhang W
DOI：
10.1038/nrm3591
发表时间：
2013-06
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
5.6
作者：
Jean-Philippe J;Paz S;Caputi M
通讯作者：
Caputi M