Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
Circ Res. 2012 Aug 17;111(5):642-56. doi: 10.1161/CIRCRESAHA.111.246546.
The silencer information regulator (Sir) family of proteins has attracted much attention during the past decade due to its prominent role in metabolic homeostasis in mammals. The Sir1-4 proteins were first discovered in yeast as nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylases, which through a gene silencing effect promoted longevity. The subsequent discovery of a homologous sirtuin (Sirt) family of proteins in the mammalian systems soon led to the realization that these molecules have beneficial effects in metabolism- and aging-related diseases. Through their concerted functions in the central nervous system, liver, pancreas, skeletal muscle, and adipose tissue, they regulate the body's metabolism. Sirt1, -6, and -7 exert their functions, predominantly, through a direct effect on nuclear transcription of genes involved in metabolism, whereas Sirt3-5 reside in the mitochondrial matrix and regulate various enzymes involved in the tricarboxylic acid and urea cycles, oxidative phosphorylation, as well as reactive oxygen species production. An interesting aspect of the functionality of sirtuin involves their regulation by the circadian rhythm, which affects their function via cyclically regulating systemic NAD(+) availability, further establishing the link of these proteins to metabolism. In this review, we will discuss the relation of sirtuins to NAD(+) metabolism, their mechanism of function, and their role in metabolism and mitochondrial functions. In addition, we will describe their effects in the cardiovascular and central nervous systems.
在过去的十年中，由于其在哺乳动物代谢稳态中的突出作用，沉默信息调节因子（Sir）家族的蛋白质引起了广泛关注。Sir1-4 蛋白最初在酵母中被发现为烟酰胺腺嘌呤二核苷酸（NAD(+))-依赖性脱乙酰酶，通过基因沉默作用促进长寿。随后在哺乳动物系统中发现了同源的 Sirtuin（Sirt）家族蛋白，这很快使人们意识到这些分子在代谢和与衰老相关的疾病中有有益的作用。通过它们在中枢神经系统、肝脏、胰腺、骨骼肌和脂肪组织中的协同作用，它们调节身体的新陈代谢。Sirt1、-6 和 -7 主要通过对涉及代谢的核转录基因的直接作用发挥其功能，而 Sirt3-5 位于线粒体基质中，调节三羧酸和尿素循环、氧化磷酸化以及活性氧产生中涉及的各种酶。Sirtuin 功能的一个有趣方面涉及它们受昼夜节律的调节，通过周期性调节系统 NAD(+) 的可用性来影响其功能，从而进一步将这些蛋白质与代谢联系起来。在这篇综述中，我们将讨论 Sirtuins 与 NAD(+) 代谢的关系、它们的作用机制以及它们在代谢和线粒体功能中的作用。此外，我们将描述它们在心血管和中枢神经系统中的作用。
