Lack of IκBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice
Lack of IκBNS promotes cholate-containing high-fat diet-induced inflammation and atherogenesis in low-density lipoprotein (LDL) receptor-deficient mice
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DOI：
10.1016/j.ijcha.2019.03.004
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发表时间：
2019-03
期刊：
影响因子：
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通讯作者：
K. Kitamura;K. Isoda;Koji Akita;Katsutoshi Miyosawa;Tomoyasu Kadoguchi;K. Shimada;H. Daida
中科院分区：
文献类型：
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作者：
K. Kitamura;K. Isoda;Koji Akita;Katsutoshi Miyosawa;Tomoyasu Kadoguchi;K. Shimada;H. Daida
背景：I κ BNS是一种核I κ B蛋白，调节Toll样受体（TLR）依赖性基因的一个亚类。含胆酸盐的高脂饮食（HFD（CA（+）诱导TLR4介导的早期炎症反应。本研究旨在阐明与喂食无胆酸盐HFD（HFD（CA（-）的小鼠相比，I κ BNS的缺乏促进了喂食HFD（CA（+））的低密度脂蛋白受体缺陷（LDLr −/−）小鼠的动脉粥样硬化形成。方法和结果：将缺乏I κ BNS的小鼠（I κ BNS-/-）与LDLr-/-小鼠杂交，并在食用HFD（CA（+））或HFD（CA（-））6周后分析动脉粥样硬化病变的形成。喂食HFD（CA（+））的I κ BNS −/−/LDLr −/−小鼠（I κ BNS −/−/LDLr −/−（CA（+）显示，与LDLr −/−（CA（+））小鼠相比，主动脉粥样硬化病变大小增加了3.5倍（p <0.01），而LDLr −/−（CA（-））和I κ BNS −/−/LDLr −/−（CA（-））小鼠之间没有差异。主动脉根部的免疫组织化学分析显示，与LDLr-/-（CA（+））小鼠相比，HFD（CA（+））使I κ BNS-/-/LDLr-/-（CA（+））小鼠中Mac-3（巨噬细胞）阳性面积显著增加1.5倍（p <0.01），TLR4、白细胞介素-6（IL-6）表达分别增加1.7倍（p <0.05）和1.5倍（p <0.05）。此外，与LDLr −/−（CA（+））小鼠相比，I κ BNS −/−/LDLr −/−（CA（+））小鼠病变中活性STAT3（pSTAT3）阳性细胞显著增加1.7倍（p <0.01）。这些发现表明I κ BNS缺乏和HFD（CA（+））通过TLR4/IL-6/STAT3途径促进LDLr −/−小鼠的动脉粥样硬化形成。最后，我们发现来自I κ BNS −/−/LDLr −/−（CA（+））小鼠外周血的单核细胞含有
Background: IκBNS, a nuclear IκB protein, regulates a subset of Toll-like receptor (TLR) dependent genes. A cholate-containing high-fat diet (HFD (CA (+))) induces TLR4 mediated early inflammatory response. The present study aims to clarify the lack of IκBNS promotes atherogenesis in low-density lipoprotein receptor-deficient (LDLr−/−) mice fed HFD (CA (+)) compared with those fed a cholate-free HFD (HFD (CA (-))). Methods and results: Mice that lacked IκBNS (IκBNS−/−) were crossed with LDLr−/− mice and formation of atherosclerotic lesions was analyzed after 6-week consumption of HFD (CA (+)) or HFD (CA (-)). IκBNS−/−/LDLr−/− mice fed HFD (CA (+))(IκBNS−/−/LDLr−/−(CA (+))) showed a 3.5-fold increase of atherosclerotic lesion size in the aorta compared with LDLr−/−(CA (+)) mice (p< 0.01), whereas there was no difference between LDLr−/−(CA (-)) and IκBNS−/−/LDLr−/−(CA (-)) mice. Immunohistochemical analysis of the aortic root revealed HFD (CA (+)) significantly increased Mac-3 (macrophage)-positive area by 1.5-fold (p< 0.01) and TLR4, interleukin-6 (IL-6) expression by 1.7-fold (p< 0.05) and 1.5-fold (p< 0.05), respectively, in IκBNS−/−/LDLr−/−(CA (+)) compared with LDLr-/-(CA (+)) mice. Furthermore, active STAT3 (pSTAT3)-positive cells were significantly increased by 1.7-fold in the lesions of IκBNS−/−/LDLr−/−(CA (+)) compared with LDLr−/−(CA (+)) mice (p< 0.01). These findings suggest that IκBNS deficiency and HFD (CA (+)) promote atherogenesis in LDLr−/− mice via TLR4/IL-6/STAT3 pathway. Finally, we showed the monocytes from peripheral blood of IκBNS−/−/LDLr−/−(CA (+)) mice were found to contain