Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT.
Elevated microRNA-34a in obesity reduces NAD+ levels and SIRT1 activity by directly targeting NAMPT.
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DOI：
10.1111/acel.12135
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发表时间：
2013-12
期刊：
影响因子：
7.8
通讯作者：
Kemper JK
中科院分区：
文献类型：
--
作者：
Choi SE;Fu T;Seok S;Kim DH;Yu E;Lee KW;Kang Y;Li X;Kemper B;Kemper JK
SIRT1是一种NAD+依赖的去乙酰化酶，参与预防许多与年龄相关的疾病，包括代谢紊乱。由于SIRT1脱乙酰酶活性依赖于NAD+水平，而直接激活SIRT1的化合物的开发一直存在争议，通过提高NAD+的生物利用度间接激活SIRT1受到越来越多的关注。肥胖和老年人的NAD+水平降低，但其潜在机制尚不清楚。我们最近发现，在肥胖中升高的肝脏microRNA-34a （miR-34a）直接靶向并降低SIRT1的表达。在这里，我们进一步证明miR-34a通过靶向NAD+生物合成的限速酶NAMPT来降低NAD+水平和SIRT1活性。在NAMPT mRNA的3 ' UTR中存在miR-34a的功能结合位点。肝脏过表达miR-34a可降低NAMPT/NAD+水平，增加SIRT1靶转录调控因子PGC-1α、SREBP-1c、FXR和NF-κB的乙酰化，导致肥胖模拟结果。NAMPT/NAD+水平的降低与miR-34a对SIRT1水平的影响无关，因为在SIRT1肝脏特异性敲除小鼠中也观察到了这一点。此外，通过NAD+中间体烟酰胺单核苷酸治疗，mir -34a介导的减少被逆转。相反，在饮食诱导的肥胖小鼠中，miR-34a的拮抗作用恢复了NAMPT/NAD+水平，减轻了脂肪变性、炎症和葡萄糖耐受不良。当NAMPT下调时，anti - mir -34a介导的NAD+水平升高减弱。我们的研究结果揭示了miR-34a在肥胖中降低SIRT1表达和活性的新功能。miR-34a/NAMPT轴是治疗涉及SIRT1功能障碍的肥胖和衰老相关疾病（如脂肪变性和2型糖尿病）的潜在靶点。
SIRT1 is an NAD+-dependent deacetylase that is implicated in prevention of many age-related diseases including metabolic disorders. Since SIRT1 deacetylase activity is dependent on NAD+ levels and the development of compounds that directly activate SIRT1 has been controversial, indirectly activating SIRT1 through enhancing NAD+ bioavailability has received increasing attention. NAD+ levels are reduced in obesity and the aged, but the underlying mechanisms remain unclear. We recently showed that hepatic microRNA-34a (miR-34a), which is elevated in obesity, directly targets and decreases SIRT1 expression. Here we further show that miR-34a reduces NAD+ levels and SIRT1 activity by targeting NAMPT, the rate-limiting enzyme for NAD+ biosynthesis. A functional binding site for miR-34a is present in the 3′ UTR of NAMPT mRNA. Hepatic overexpression of miR-34a reduced NAMPT/NAD+ levels, increased acetylation of the SIRT1 target transcriptional regulators, PGC-1α, SREBP-1c, FXR, and NF-κB, and resulted in obesity-mimetic outcomes. The decreased NAMPT/NAD+ levels were independent of miR-34a effects on SIRT1 levels since they were also observed in SIRT1 liver-specific knockout mice. Further, the miR-34a-mediated decreases were reversed by treatment with the NAD+ intermediate, nicotinamide mononucleotide. Conversely, antagonism of miR-34a in diet-induced obese mice restored NAMPT/NAD+ levels and alleviated steatosis, inflammation, and glucose intolerance. Anti-miR-34a-mediated increases in NAD+ levels were attenuated when NAMPT was downregulated. Our findings reveal a novel function of miR-34a in reducing both SIRT1 expression and activity in obesity. The miR-34a/NAMPT axis presents a potential target for treating obesity- and aging-related diseases involving SIRT1 dysfunction like steatosis and type 2 diabetes.
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DOI：
10.1126/science.1231097
发表时间：
2013-03-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hubbard BP;Gomes AP;Dai H;Li J;Case AW;Considine T;Riera TV;Lee JE;E SY;Lamming DW;Pentelute BL;Schuman ER;Stevens LA;Ling AJ;Armour SM;Michan S;Zhao H;Jiang Y;Sweitzer SM;Blum CA;Disch JS;Ng PY;Howitz KT;Rolo AP;Hamuro Y;Moss J;Perni RB;Ellis JL;Vlasuk GP;Sinclair DA
通讯作者：
Sinclair DA
影响因子：
64.8
作者：
Guarente, Leonard
通讯作者：
Guarente, Leonard
影响因子：
4.8
作者：
Pacholec, Michelle;Bleasdale, John E.;Ahn, Kay
通讯作者：
Ahn, Kay
靶向Sirtuin 1以改善新陈代谢：您所需要的是NAD（+）？
影响因子：
21.1
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J
DOI：
10.1146/annurev.pathol.4.110807.092250
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Haigis MC;Sinclair DA
通讯作者：
Sinclair DA