Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
Mol Cell Biochem. 2010 Jun;339(1-2):285-92. doi: 10.1007/s11010-010-0391-z. Epub 2010 Feb 11.
Calorie restriction (CR) extends lifespans in a wide variety of species. CR induces an increase in the NAD(+)/NADH ratio in cells and results in activation of SIRT1, an NAD(+)-dependent protein deacetylase that is thought to be a metabolic master switch linked to the modulation of lifespans. CR also affects the expression of peroxisome proliferator-activated receptors (PPARs). The three subtypes, PPARalpha, PPARgamma, and PPARbeta/delta, are expressed in multiple organs. They regulate different physiological functions such as energy metabolism, insulin action and inflammation, and apparently act as important regulators of longevity and aging. SIRT1 has been reported to repress the PPARgamma by docking with its co-factors and to promote fat mobilization. However, the correlation between SIRT1 and other PPARs is not fully understood. CR initially induces a fasting-like response. In this study, we investigated how SIRT1 and PPARalpha correlate in the fasting-induced anti-aging pathways. A 24-h fasting in mice increased mRNA and protein expression of both SIRT1 and PPARalpha in the livers, where the NAD(+) levels increased with increasing nicotinamide phosphoribosyltransferase (NAMPT) activity in the NAD(+) salvage pathway. Treatment of Hepa1-6 cells in a low glucose medium conditions with NAD(+) or NADH showed that the mRNA expression of both SIRT1 and PPARalpha can be enhanced by addition of NAD(+), and decreased by increasing NADH levels. The cell experiments using SIRT1 antagonists and a PPARalpha agonist suggested that PPARalpha is a key molecule located upstream from SIRT1, and has a role in regulating SIRT1 gene expression in fasting-induced anti-aging pathways.
热量限制（CR）可延长多种物种的寿命。CR 会增加细胞中的 NAD(+) / NADH 比值，从而激活 SIRT1，SIRT1 是一种依赖 NAD(+) 的蛋白去乙酰化酶，被认为是与寿命调节相关的代谢主开关。CR 还会影响过氧化物酶体增殖物激活受体（PPARs）的表达。三种亚型，PPARalpha、PPARgamma 和 PPARbeta/delta，在多个器官中表达。它们调节不同的生理功能，如能量代谢、胰岛素作用和炎症，显然作为长寿和衰老的重要调节剂。据报道，SIRT1 通过与其共因子结合来抑制 PPARgamma，并促进脂肪动员。然而，SIRT1 与其他 PPARs 之间的相关性尚未完全阐明。CR 最初会诱导类似禁食的反应。在这项研究中，我们研究了 SIRT1 和 PPARalpha 如何在禁食诱导的抗衰老途径中相关。在小鼠中进行 24 小时禁食会增加肝脏中 SIRT1 和 PPARalpha 的 mRNA 和蛋白表达，同时 NAD(+) 水平随着 NAD(+) 补救途径中烟酰胺磷酸核糖基转移酶（NAMPT）活性的增加而增加。在低糖培养基条件下用 NAD(+) 或 NADH 处理 Hepa1-6 细胞表明，添加 NAD(+) 可以增强 SIRT1 和 PPARalpha 的 mRNA 表达，而增加 NADH 水平则会降低其表达。使用 SIRT1 拮抗剂和 PPARalpha 激动剂的细胞实验表明，PPARalpha 是位于 SIRT1 上游的关键分子，在调节禁食诱导的抗衰老途径中的 SIRT1 基因表达中起作用。
