Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet.
Toll-like receptor 4 knockout mice are protected against endoplasmic reticulum stress induced by a high-fat diet.
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DOI：
10.1371/journal.pone.0065061
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Francaux M
中科院分区：
文献类型：
--
作者：
Pierre N;Deldicque L;Barbé C;Naslain D;Cani PD;Francaux M
本研究的目的是探讨Toll样受体4（TLR 4）是否与高脂饮食（HFD）后肝脏、骨骼肌和脂肪组织中观察到的内质网应激（ER应激）的发展有关。TLR 4-/-和C57 BL/6 J野生型小鼠（WT）在18周内喂食食物或HFD（45%卡路里来自脂肪）。进行口服葡萄糖耐量试验。在禁食状态下处死动物，并取出组织。TLR 4缺失保护HFD诱导的体重增加和葡萄糖耐受不良，而转基因小鼠的能量摄入更高，表明能量消耗更大。通过BiP、CHOP、剪接和未剪接的XBP 1和磷酸化eIF 2 α评估，HFD诱导WT小鼠骨骼肌、肝脏和脂肪组织中的ER应激。TLR 4 −/−小鼠受到HFD诱导的ER应激的保护。然后，我们研究了TLR 4下游的主要信号通路即NF-κB通路，以期明确TLR 4激活ER应激的机制。HFD后NF-κB调控的细胞因子TNFα、IL-1β和IL-6的mRNA水平无变化，磷酸化I κB-α（ser 32）无变化。我们的研究结果表明，TLR 4是必不可少的发展与HFD相关的ER应力。然而，NFκ-B通路似乎并不直接参与。TLR 4 −/−小鼠脂肪储存减少可以解释HFD后缺乏ER应激。
The purpose of this study was to investigate whether toll-like receptor 4 (TLR4) is implicated in the development of endoplasmic reticulum stress (ER stress) observed after a high-fat diet (HFD) in liver, skeletal muscle and adipose tissue. TLR4−/− and C57BL/6J wild-type mice (WT) were fed with chow or HFD (45% calories from fat) during 18 weeks. An oral glucose tolerance-test was performed. The animals were sacrificed in a fasted state and the tissues were removed. TLR4 deletion protected from body weight gain and glucose intolerance induced by HFD whereas energy intake was higher in transgenic mice suggesting larger energy expenditure. HFD induced an ER stress in skeletal muscle, liver and adipose tissue of WT mice as assessed by BiP, CHOP, spliced and unspliced XBP1 and phospho-eIF2α. TLR4−/− mice were protected against HFD-induced ER stress. Then, we investigated the main signaling downstream of TLR4 namely the NF-κB pathway, expecting to identify the mechanism by which TLR4 is able to activate ER stress. The mRNA levels of cytokines regulated by NF-κB namely TNFα, IL-1β and IL-6, were not changed after HFD and phospho-IκB-α (ser 32) was not changed. Our results indicate that TLR4 is essential for the development of ER stress related to HFD. Nevertheless, the NFκ-B pathway does not seem to be directly implicated. The reduced fat storage in TLR4−/− mice could explain the absence of an ER stress after HFD.
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