Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation
Isoliquiritigenin is a potent inhibitor of NLRP3 inflammasome activation and diet-induced adipose tissue inflammation
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DOI：
10.1189/jlb.3a0114-005rr
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发表时间：
2014-12-01
影响因子：
5.5
通讯作者：
Takatsu, Kiyoshi
中科院分区：
文献类型：
--
作者：
Honda, Hiroe;Nagai, Yoshinori;Takatsu, Kiyoshi
异甘草素是甘草的一种成分，是NLRP3炎性体的有效抑制剂，可抑制饮食诱导的肥胖、脂肪组织炎症和代谢紊乱。炎性小体的激活引发了许多炎症性疾病的发展，包括肥胖和2型糖尿病。因此，靶向离散激活步骤的药物可能代表非常重要的药物。我们之前报道过甘草查尔酮ILG抑制lps诱导的NF-B激活。在这里，我们发现ILG可以有效抑制NLRP3炎性体的激活，并且这种作用独立于其对TLR4的抑制效力。ILG的抑制作用比parthenolide强，parthenolide是一种已知的NLRP3炎性体的抑制剂。甘草三萜GL对NLRP3活性也有类似的抑制作用，但需要高浓度的GL。相比之下，AIM2炎性体的激活被GL抑制，而不被ILG抑制。此外，GL抑制NLRP3-和aim2激活的ASC寡聚化，而ILG抑制NLRP3激活的ASC寡聚化。与磺脲类药物格列本脲相比，低浓度的ILG对iapp诱导的IL-1产生非常有效。体内分析显示，ILG能有效减轻hfd诱导的肥胖、高胆固醇血症和胰岛素抵抗。此外，ILG治疗改善了hfd诱导的肝脏大泡性脂肪变性。最后，在离体培养中，ILG显著抑制饮食诱导的脂肪组织炎症和白色脂肪组织中IL-1和caspase-1的产生。这些结果表明，ILG是治疗NLRP3炎性小体相关炎症性疾病的潜在药物靶点。
Isoliquiritigenin, a component of Glycyrrhiza uralensis, is a potent inhibitor of the NLRP3 inflammasome, and suppresses diet-induced obesity, adipose tissue inflammation, and metabolic disorders. Inflammasome activation initiates the development of many inflammatory diseases, including obesity and type 2 diabetes. Therefore, agents that target discrete activation steps could represent very important drugs. We reported previously that ILG, a chalcone from Glycyrrhiza uralensis, inhibits LPS-induced NF-B activation. Here, we show that ILG potently inhibits the activation of NLRP3 inflammasome, and the effect is independent of its inhibitory potency on TLR4. The inhibitory effect of ILG was stronger than that of parthenolide, a known inhibitor of the NLRP3 inflammasome. GL, a triterpenoid from G. uralensis, had similar inhibitory effects on NLRP3 activity, but high concentrations of GL were required. In contrast, activation of the AIM2 inflammasome was inhibited by GL but not by ILG. Moreover, GL inhibited NLRP3- and AIM2-activated ASC oligomerization, whereas ILG inhibited NLRP3-activated ASC oligomerization. Low concentrations of ILG were highly effective in IAPP-induced IL-1 production compared with the sulfonylurea drug glyburide. In vivo analyses revealed that ILG potently attenuated HFD-induced obesity, hypercholesterolemia, and insulin resistance. Furthermore, ILG treatment improved HFD-induced macrovesicular steatosis in the liver. Finally, ILG markedly inhibited diet-induced adipose tissue inflammation and IL-1 and caspase-1 production in white adipose tissue in ex vivo culture. These results suggest that ILG is a potential drug target for treatment of NLRP3 inflammasome-associated inflammatory diseases.