PDF(Pubmed)
Abstract：
Silent information regulator two homolog 1 (SIRT1), an NAD + -dependent histone deacetylase, plays a pivotal regulatory role in a myriad of physiological processes. A growing body of evidence suggests that SIRT1 can exert protective effects in metabolic disorders and neurodegenerative diseases by inhibiting endoplasmic reticulum (ER) stress and the nuclear factor-κB (NF-κB) inflammatory signaling pathway. This review systematically elucidates the molecular mechanisms and biological significance of SIRT1 in regulating ER stress and the NF-κB pathway. On one hand, SIRT1 can deacetylate key molecules in the ER stress pathway, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), PKR-like ER kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor 6 (ATF6), thereby alleviating ER stress. On the other hand, SIRT1 can directly or indirectly remove the acetylation modification of the NF-κB p65 subunit, inhibiting its transcriptional activity and thus attenuating inflammatory responses. Through these mechanisms, SIRT1 can ameliorate insulin resistance in metabolic diseases, exert cardioprotective effects in ischemia-reperfusion injury, and reduce neuronal damage in neurodegenerative diseases. However, it is important to note that while these findings are promising, the complex nature of the biological systems involved warrants further investigation to fully unravel the intricacies of SIRT1\'s regulatory mechanisms. Nevertheless, understanding the regulatory mechanisms of SIRT1 on ER stress and the NF-κB pathway is of great significance for expanding our knowledge of the pathogenesis of related diseases and exploring new preventive and therapeutic strategies targeting SIRT1.
摘要：
无声信息调节器两个同源物1(SIRT1)，NAD+依赖性组蛋白脱乙酰酶，在无数的生理过程中起着关键的调节作用。越来越多的证据表明，SIRT1可以通过抑制内质网（ER）应激和核因子-κB（NF-κB）炎症信号通路在代谢紊乱和神经退行性疾病中发挥保护作用。本文就SIRT1调控ER应激和NF-κB通路的分子机制及其生物学意义作一综述。一方面,SIRT1可以使ER应激途径中的关键分子脱乙酰，如葡萄糖调节蛋白78（GRP78），X盒结合蛋白1（XBP1），PKR样ER激酶(PERK),需要肌醇的酶1α（IRE1α），和激活转录因子6（ATF6），从而缓解ER压力。另一方面,SIRT1可以直接或间接去除NF-κBp65亚基的乙酰化修饰，抑制其转录活性，从而减弱炎症反应。通过这些机制,SIRT1可以改善代谢性疾病中的胰岛素抵抗，在缺血再灌注损伤中发挥心脏保护作用，减少神经退行性疾病中的神经元损伤。然而,重要的是要注意，虽然这些发现是有希望的，所涉及的生物系统的复杂性需要进一步研究，以完全解开SIRT1调控机制的复杂性。然而，了解SIRT1对ER应激和NF-κB通路的调控机制,对于拓展我们对相关疾病发病机制的认识,探索针对SIRT1的新的预防和治疗策略具有重要意义。
