TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with diet-induced type 2 diabetes.
TLR4 antagonist attenuates atherogenesis in LDL receptor-deficient mice with diet-induced type 2 diabetes.
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DOI：
10.1016/j.imbio.2015.06.016
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发表时间：
2015-11
期刊：
影响因子：
2.8
通讯作者：
Huang Y
中科院分区：
文献类型：
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作者：
Lu Z;Zhang X;Li Y;Lopes-Virella MF;Huang Y
尽管大量研究已经证实了Toll样受体（TLR）4在动脉粥样硬化中的关键作用，但TLR 4拮抗剂是否能减轻2型糖尿病小鼠模型中的动脉粥样硬化形成仍不确定。在这项研究中，我们通过高脂饮食（HFD）诱导低密度脂蛋白受体缺陷（LDLR−/−）小鼠发生2型糖尿病。在8周龄时，20只小鼠喂食HFD，20只小鼠喂食常规食物（RC）24周。在最后10周，一半HFD喂养的小鼠和一半RC喂养的小鼠用类球形红杆菌脂多糖（Rs-LPS）（一种确定的TLR 4拮抗剂）处理。治疗后对动脉粥样硬化病变进行分析。结果显示，HFD显著增加体重、葡萄糖、脂质（包括总胆固醇、甘油三酯和游离脂肪酸）和胰岛素抵抗，表明HFD在LDLR−/−小鼠中诱导2型糖尿病。结果还表明，在非糖尿病和糖尿病小鼠中，Rs-LPS对HFD增加的代谢参数没有影响。动脉粥样硬化的脂质染色和主动脉根部横截面的组织学分析表明，糖尿病增加动脉粥样硬化病变，但Rs-LPS衰减糖尿病小鼠的动脉粥样硬化形成。免疫组化结果显示，Rs-LPS可降低糖尿病小鼠动脉粥样硬化病变中单核/巨噬细胞浸润及白细胞介素（IL）-6和基质金属蛋白酶-9的表达。最后，通过我们的体外研究证实了Rs-LPS对TLR 4的拮抗作用，表明Rs-LPS抑制由LPS或LPS加饱和脂肪酸棕榈酸酯刺激的巨噬细胞和内皮细胞分泌IL-6。总之，我们的研究表明，TLR 4拮抗剂能够减轻血管炎症和动脉粥样硬化形成的小鼠与HFD诱导的2型糖尿病。
Although a large number of studies have well documented a key role of toll-like receptor (TLR)4 in atherosclerosis, it remains undetermined if TLR4 antagonist attenuates atherogenesis in mouse model for type 2 diabetes. In this study, we induced type 2 diabetes in low-density lipoprotein receptor-deficient (LDLR−/−) mice by high-fat diet (HFD). At 8 weeks old, 20 mice were fed HFD and 20 mice fed regular chow (RC) for 24 weeks. In the last 10 weeks, half HFD-fed mice and half RC-fed mice were treated with Rhodobacter sphaeroides lipopolysaccharide (Rs-LPS), an established TLR4 antagonist. After the treatment, atherosclerotic lesions in aortas were analyzed. Results showed that the HFD significantly increased bodyweight, glucose, lipids including total cholesterol, triglycerides and free fatty acids, and insulin resistance, indicating that the HFD induced type 2 diabetes in LDLR−/− mice. Results also showed that Rs-LPS had no effect on HFD-increased metabolic parameters in both nondiabetic and diabetic mice. Lipid staining of aortas and histological analysis of cross-sections of aortic roots showed that diabetes increased atherosclerotic lesions, but Rs-LPS attenuated atherogenesis in diabetic mice. Furthermore, immunohistochemical studies showed that Rs-LPS reduced infiltration of monocytes/macrophages and expression of interleukin (IL)-6 and matrix metalloproteinase-9 in atherosclerotic lesions of diabetic mice. Finally, the antagonistic effect of Rs-LPS on TLR4 was demonstrated by our in vitro studies showing that Rs-LPS inhibited IL-6 secretion from macrophages and endothelial cells stimulated by LPS or LPS plus saturated fatty acid palmitate. Taken together, our study demonstrated that TLR4 antagonist was capable of attenuating vascular inflammation and atherogenesis in mice with HFD-induced type 2 diabetes.