Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice
Fasting promotes the expression of SIRT1, an NAD+-dependent protein deacetylase, via activation of PPARα in mice
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DOI：
10.1007/s11010-010-0391-z
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发表时间：
2010-06-01
影响因子：
4.3
通讯作者：
Soeda, Shinji
中科院分区：
文献类型：
--
作者：
Hayashida, Satoru;Arimoto, Akie;Soeda, Shinji
热量限制（CR）延长了许多物种的寿命。CR诱导细胞中NAD（+）/NADH比率增加，并导致SIRT 1激活，SIRT 1是一种NAD（+）依赖性蛋白脱乙酰酶，被认为是与寿命调节相关的代谢主开关。CR还影响过氧化物酶体增殖物激活受体（PPARs）的表达。这三种亚型，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，显然是长寿和衰老的重要调节因子。据报道，SIRT 1通过与其辅因子对接来抑制PPAR γ，并促进脂肪动员。然而，SIRT 1和其他PPARs之间的相关性尚未完全了解。CR最初诱导禁食样反应。在这项研究中，我们研究了SIRT 1和PPAR α在禁食诱导的抗衰老途径中如何相互关联。小鼠禁食24小时增加了肝脏中SIRT 1和PPAR α的mRNA和蛋白表达，其中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。用NAD（+）或NADH处理低糖培养的Hepa 1 -6细胞，结果表明，加入NAD（+）可增强SIRT 1和PPAR α的mRNA表达，而增加NADH水平则可降低SIRT 1和PPAR α的mRNA表达。使用SIRT 1拮抗剂和PPAR α激动剂的细胞实验表明，PPAR α是位于SIRT 1上游的关键分子，在禁食诱导的抗衰老途径中调节SIRT 1基因表达。
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, PPAR alpha, PPAR gamma, and PPAR beta/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 PPAR gamma 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 PPAR alpha correlate in the fasting-induced anti-aging pathways. A 24-h fasting in mice increased mRNA and protein expression of both SIRT1 and PPAR alpha 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 PPAR alpha can be enhanced by addition of NAD(+), and decreased by increasing NADH levels. The cell experiments using SIRT1 antagonists and a PPAR alpha agonist suggested that PPAR alpha is a key molecule located upstream from SIRT1, and has a role in regulating SIRT1 gene expression in fasting-induced anti-aging pathways.