Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.
Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.
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DOI：
10.2337/db14-0667
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发表时间：
2015-04
期刊：
影响因子：
7.7
通讯作者：
Schrauwen P
中科院分区：
文献类型：
--
作者：
van de Weijer T;Phielix E;Bilet L;Williams EG;Ropelle ER;Bierwagen A;Livingstone R;Nowotny P;Sparks LM;Paglialunga S;Szendroedi J;Havekes B;Moullan N;Pirinen E;Hwang JH;Schrauwen-Hinderling VB;Hesselink MK;Auwerx J;Roden M;Schrauwen P
最近的临床前研究表明，烟酰胺腺嘌呤二核苷酸（NAD+）前体有可能增加氧化磷酸化并改善代谢健康，但缺乏人体数据。我们假设烟酸衍生物阿昔莫司（一种NAD+前体）将直接影响线粒体功能，而不依赖于非酯化脂肪酸（NEFA）浓度的降低。在一项多中心随机交叉试验中，21例2型糖尿病患者（年龄57.7 ± 1.1岁，BMI 33.4 ± 0.8 kg/m2）接受安慰剂或阿昔莫司250 mg每日3次给药，持续2周。由于先前描述的反跳效应，阿昔莫司治疗增加了血浆NEFA水平（759 ± 44 vs. 1，135 ± 97 μmol/L，安慰剂vs.阿昔莫司，P < 0.01）。结果，骨骼肌脂质含量增加，胰岛素敏感性降低。尽管血浆NEFA水平升高，但骨骼肌中的离体线粒体呼吸增加。随后，我们发现阿昔莫司治疗导致核编码的线粒体基因组表达的强烈升高和线粒体蛋白质失衡，这可能表明线粒体未折叠蛋白反应的激活。在C2 C12肌管中的进一步研究证实了阿昔莫司对NAD+水平、线粒体蛋白质失衡和线粒体氧化能力的直接影响。据我们所知，这项研究是第一个证明NAD+助推器也可以直接影响人类骨骼肌线粒体功能的研究。
Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD+) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD+ precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 ± 1.1 years, BMI 33.4 ± 0.8 kg/m2) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 ± 44 vs. 1,135 ± 97 μmol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD+ levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD+ boosters can also directly affect skeletal muscle mitochondrial function in humans.
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影响因子：
29
作者：
Bai P;Canto C;Brunyánszki A;Huber A;Szántó M;Cen Y;Yamamoto H;Houten SM;Kiss B;Oudart H;Gergely P;Menissier-de Murcia J;Schreiber V;Sauve AA;Auwerx J
通讯作者：
Auwerx J
影响因子：
7.7
作者：
Hoeks J;van Herpen NA;Mensink M;Moonen-Kornips E;van Beurden D;Hesselink MK;Schrauwen P
通讯作者：
Schrauwen P
DOI：
10.1126/science.1171641
发表时间：
2009-05-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ramsey KM;Yoshino J;Brace CS;Abrassart D;Kobayashi Y;Marcheva B;Hong HK;Chong JL;Buhr ED;Lee C;Takahashi JS;Imai S;Bass J
通讯作者：
Bass J
影响因子：
15.9
作者：
Benyó, Z;Gille, A;Offermanns, S
通讯作者：
Offermanns, S
影响因子：
7.7
作者：
Meex RC;Schrauwen-Hinderling VB;Moonen-Kornips E;Schaart G;Mensink M;Phielix E;van de Weijer T;Sels JP;Schrauwen P;Hesselink MK
通讯作者：
Hesselink MK