Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.
Flavonoid apigenin is an inhibitor of the NAD+ ase CD38: implications for cellular NAD+ metabolism, protein acetylation, and treatment of metabolic syndrome.
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作者：
Escande C;Nin V;Price NL;Capellini V;Gomes AP;Barbosa MT;O'Neil L;White TA;Sinclair DA;Chini EN
代谢综合征是一个日益严重的全球性健康问题。因此，必须制定新的策略来治疗这种病理学。在过去的几年中，NAD+代谢的操纵已成为改善代谢综合征的合理策略。特别是，细胞NAD+水平的增加具有有益效果，可能是因为sirtuins的激活。在此之前，我们报道了CD 38是哺乳动物中主要的NAD+酶。此外，CD 38基因敲除小鼠具有更高的NAD+水平，并且可以预防肥胖和代谢综合征。在这里，我们表明，CD 38通过NAD+水平和sirtuin活性的变化调节全球蛋白质乙酰化。此外，我们表征了两种CD 38抑制剂：槲皮素和芹菜素。我们表明，药理学抑制CD 38的结果在更高的细胞内NAD+水平和芹菜素的细胞培养物的治疗降低全球乙酰化以及乙酰化的p53和RelA-p65。最后，向肥胖小鼠施用芹菜素增加NAD+水平，降低整体蛋白质乙酰化，并改善葡萄糖和脂质稳态的几个方面。我们的研究结果表明，CD 38是一种新的药理学靶点，通过NAD+依赖性途径治疗代谢性疾病。
Metabolic syndrome is a growing health problem worldwide. It is therefore imperative to develop new strategies to treat this pathology. In the past years, the manipulation of NAD+ metabolism has emerged as a plausible strategy to ameliorate metabolic syndrome. In particular, an increase in cellular NAD+ levels has beneficial effects, likely because of the activation of sirtuins. Previously, we reported that CD38 is the primary NAD+ase in mammals. Moreover, CD38 knockout mice have higher NAD+ levels and are protected against obesity and metabolic syndrome. Here, we show that CD38 regulates global protein acetylation through changes in NAD+ levels and sirtuin activity. In addition, we characterize two CD38 inhibitors: quercetin and apigenin. We show that pharmacological inhibition of CD38 results in higher intracellular NAD+ levels and that treatment of cell cultures with apigenin decreases global acetylation as well as the acetylation of p53 and RelA-p65. Finally, apigenin administration to obese mice increases NAD+ levels, decreases global protein acetylation, and improves several aspects of glucose and lipid homeostasis. Our results show that CD38 is a novel pharmacological target to treat metabolic diseases via NAD+-dependent pathways.
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影响因子：
120.7
作者：
Hedley, AA;Ogden, CL;Flegal, KM
通讯作者：
Flegal, KM
影响因子：
4.8
作者：
Pacholec, Michelle;Bleasdale, John E.;Ahn, Kay
通讯作者：
Ahn, Kay
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
DOI：
10.1158/1078-0432.ccr-10-0939
发表时间：
2010-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Anders CK;Winer EP;Ford JM;Dent R;Silver DP;Sledge GW;Carey LA
通讯作者：
Carey LA
影响因子：
64.8
作者：
Baur, Joseph A.;Pearson, Kevin J.;Sinclair, David A.
通讯作者：
Sinclair, David A.