Department of Biochemistry, Yong Loo Lin School of Medicine, National University Health System, National University of Singapore, 8 Medical Drive, Singapore.
Biochem Biophys Res Commun. 2010 Jan 1;391(1):6-10. doi: 10.1016/j.bbrc.2009.11.016. Epub 2009 Nov 11.
Sir2/Sirt1, a mediator of longevity in several animal models, is a member of the sirtuin family of type III histone deacetylases. Its non-histone substrates include a group of regulatory molecules that modulate energy metabolism, such as peroxisome proliferator-activated receptor-gamma (PPARgamma), and its transcriptional coactivator, PPARgammacoactivator-1alpha (PGC-1alpha). Sirt1's activity on these substrates may underlie its connection with the metabolic changes brought about by caloric restriction (CR). Recent studies have elucidated new substrates for Sirt1 that are involved in metabolic regulation, and have further delineated Sirt1's functional associations with other metabolic regulators like AMP-activated kinase (AMPK). Perplexingly, manipulations that either increase or decrease Sirt1 activity have both been associated with a beneficial effect in animal models of ageing-associated disorders, such as neurodegenerative diseases. Sirt1's activation patterns and roles in energy metabolism appear to have tissue specific differences. A deeper understanding of the mechanistic underpinnings of Sirt1's metabolic functions is necessary to effectively design Sirt1-based therapeutic interventions for metabolic disorders.
Sir2/Sirt1 是几种动物模型中长寿的介质，是 III 类组蛋白去乙酰化酶的 sirtuin 家族的成员。其非组蛋白底物包括一组调节分子，这些调节分子可调节能量代谢，如过氧化物酶体增殖物激活受体-γ (PPARγ)及其转录共激活因子过氧化物酶体增殖物激活受体γ辅激活因子 1α (PGC-1α)。Sirt1 对这些底物的活性可能是其与热量限制 (CR) 引起的代谢变化有关的基础。最近的研究阐明了 Sirt1 的新底物，这些底物参与代谢调节，并进一步描述了 Sirt1 与其他代谢调节剂如 AMP 激活的蛋白激酶 (AMPK) 的功能关联。令人费解的是，增加或减少 Sirt1 活性的操作都与衰老相关疾病（如神经退行性疾病）的动物模型中的有益效果有关。Sirt1 的激活模式及其在能量代谢中的作用似乎具有组织特异性差异。为了有效设计基于 Sirt1 的代谢紊乱治疗干预措施，有必要深入了解 Sirt1 代谢功能的机制基础。
