Activation of PPARγ by a Natural Flavonoid Modulator, Apigenin Ameliorates Obesity-Related Inflammation Via Regulation of Macrophage Polarization.
Activation of PPARγ by a Natural Flavonoid Modulator, Apigenin Ameliorates Obesity-Related Inflammation Via Regulation of Macrophage Polarization.
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DOI：
10.1016/j.ebiom.2016.06.017
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发表时间：
2016-07
期刊：
影响因子：
11.1
通讯作者：
Shen P
中科院分区：
文献类型：
--
作者：
Feng X;Weng D;Zhou F;Owen YD;Qin H;Zhao J;WenYu;Huang Y;Chen J;Fu H;Yang N;Chen D;Li J;Tan R;Shen P
过氧化物酶体增殖物激活受体γ（PPARγ）已成为巨噬细胞极化的主要调节因子，也是噻唑烷二酮类药物的分子靶点。在此，我们表明芹菜素作为一种调节剂，能够结合并激活PPARγ。芹菜素对PPARγ的激活通过抑制p65/PPARγ复合物向细胞核的转运，从而阻止p65向细胞核转运，进而降低核因子κB（NF-κB）的激活，促进M2型巨噬细胞极化。在高脂饮食（HFD）小鼠和ob/ob小鼠中，芹菜素显著地将M1型巨噬细胞逆转为M2型，减少肝脏和脂肪组织中炎症细胞的浸润，并降低促炎细胞因子水平，从而减轻炎症。引人注目的是，芹菜素减轻了肝脏和肌肉的脂肪变性，降低了丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆固醇（TC）和甘油三酯（TG）的水平，明显改善了葡萄糖抵抗。与罗格列酮不同，芹菜素不会导致体重显著增加、骨质疏松等情况。我们的研究结果确定芹菜素是PPARγ的调节剂，也是治疗代谢紊乱的潜在先导化合物。
芹菜素结合并激活PPARγ，显著地将巨噬细胞的极化从M1表型逆转为M2表型。
芹菜素对PPARγ的激活通过抑制p65/PPARγ复合物向细胞核的转运来阻止p65转运。
芹菜素显著减轻代谢炎症和紊乱，且不会像噻唑烷二酮类药物那样产生一些副作用。
PPARγ是噻唑烷二酮类药物治疗2型糖尿病的分子靶点。然而，噻唑烷二酮类药物存在一些副作用，包括心力衰竭、肝毒性、骨折和潜在致癌性，这极大地限制了它们的临床应用。在此，我们发现芹菜素，一种在各种水果和蔬菜中大量存在的类黄酮分子，能够调控巨噬细胞的分化命运，抑制炎症和代谢综合征，且不会像噻唑烷二酮类药物那样产生一些副作用。进一步研究表明，芹菜素可以作用于PPARγ并产生一系列有益效果，可能成为开发针对代谢紊乱新疗法的先导化合物。
PPARγ has emerged as a master regulator of macrophage polarization and is the molecular target of the thiazolidinedione drugs. Here we show that apigenin binds and activates PPARγ by acting as a modulator. Activation of PPARγ by apigenin blocks p65 translocation into nuclei through inhibition of p65/PPARγ complex translocation into nuclei, thereby decreasing NF-κB activation and favoringM2 macrophage polarization. In HFD and ob/ob mice, apigenin significantly reverses M1 macrophage into M2 and reduces the infiltration of inflammatory cells in liver and adipose tissues, as well as decreases the levels of pro-inflammatory cytokines, thereby alleviating inflammation. Strikingly, apigenin reduces liver and muscular steatosis, decreases the levels of ALT, AST, TC and TG, improving glucose resistance obviously. Unlike rosiglitazone, apigenin does not cause significant weight gain, osteoporosis et al. Our findings identify apigenin as a modulator of PPARγ and a potential lead compound for treatment of metabolic disorders. Apigenin binds and activates PPARγ and significantly reverses the polarization of macrophages from M1 to M2 phenotype. Activation of PPARγ by apigenin blocks p65 translocation through inhibiting p65/PPARγ complex translocation into nucleus. Apigenin significantly attenuates metabolic inflammation and disorders without causing some side effects as TZD drugs do. PPARγ is the molecular target of the thiazolidinedione drugs to treat type II diabetes. However, TZD drugs have some side effects including cardiovascular failure, liver toxicity, bone fractures and potential carcinogenesis, which have greatly limited their clinical use. Here, we find apigenin, a flavonoid molecule abundant in various fruits and vegetables, can control macrophage fate to inhibit inflammation and metabolic syndrome without causing some side effects as TZD drugs. Further study indicates that apigenin can target PPARγ with a range of beneficial effects and may represent a lead compound for developing new therapies against metabolic disorders.