Reduced Paneth cell antimicrobial protein levels correlate with activation of the unfolded protein response in the gut of obese individuals
Reduced Paneth cell antimicrobial protein levels correlate with activation of the unfolded protein response in the gut of obese individuals
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DOI：
10.1002/path.2917
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发表时间：
2011-10-01
影响因子：
7.3
通讯作者：
Lenaerts, Kaatje
中科院分区：
文献类型：
--
作者：
Hodin, Caroline M.;Verdam, Froukje J.;Lenaerts, Kaatje
越来越多的人认识到肠道微生物群在肥胖的发展中起着至关重要的作用。在肥胖受试者中观察到肠道微生物群组成的变化，其有利于厚壁菌门而不是拟杆菌门的存在。在缺乏活性潘氏细胞α-防御素的小鼠中也报道了类似的变化。我们的目的是调查的变化潘氏细胞抗菌剂水平在肠道的肥胖受试者。接下来，我们研究了未折叠蛋白反应（UPR）的激活，这可能是潘氏细胞功能改变的一种机制。对15例重度肥胖（BMI > 35）和15例正常体重受试者的空肠切片进行潘氏细胞计数。使用免疫组织化学、qPCR和蛋白质印迹研究潘氏细胞抗菌剂人α-防御素5（HD 5）和溶菌酶的表达。用蛋白质印迹法评估UPR的活化。严重肥胖的受试者显示HD 5和溶菌酶的蛋白质水平降低，而潘氏细胞数量不变。溶菌酶蛋白水平与BMI呈负相关。HD 5（DEFA 5）和溶菌酶（LYZ）的转录本在肥胖受试者的肠道中的表达增加，促使我们研究UPR激活引起的可能的翻译阻断。结合蛋白（BiP）和激活转录因子4（ATF 4）水平增加，证实了肥胖受试者肠道中UPR的激活。此外，这两种蛋白质的水平与BMI相关。BiP水平和溶菌酶水平之间的负相关性强烈表明UPR参与肥胖受试者中抗菌蛋白水平的降低。此外，ER应激的迹象在肥胖受试者的潘氏细胞中是明显的。我们的研究结果为肥胖症患者潘氏细胞功能的改变提供了第一个证据，这可能对与肥胖相关的微生物群组成的变化具有重要意义。此外，我们发现在肥胖受试者的肠道中UPR的激活，这可能是观察到的潘氏细胞妥协的基础。版权所有（C）2011大不列颠和爱尔兰病理学会。出版社：John Wiley & Sons，Ltd
The intestinal microbiota is increasingly acknowledged to play a crucial role in the development of obesity. A shift in intestinal microbiota composition favouring the presence of Firmicutes over Bacteroidetes has been observed in obese subjects. A similar shift has been reported in mice with deficiency of active Paneth cell alpha-defensins. We aimed at investigating changes in Paneth cell antimicrobial levels in the gut of obese subjects. Next, we studied activation of the unfolded protein response (UPR) as a possible mechanism involved in altered Paneth cell function. Paneth cell numbers were counted in jejunal sections of 15 severely obese (BMI > 35) and 15 normal weight subjects. Expression of Paneth cell antimicrobials human alpha-defensin 5 (HD5) and lysozyme were investigated using immunohistochemistry, qPCR, and western blot. Activation of the UPR was assessed with western blot. Severely obese subjects showed decreased protein levels of both HD5 and lysozyme, while Paneth cell numbers were unchanged. Lysozyme protein levels correlated inversely with BMI. Increased expression of HD5 (DEFA5) and lysozyme (LYZ) transcripts in the intestine of obese subjects prompted us to investigate a possible translational block caused by UPR activation. Binding protein (BiP) and activating transcription factor 4 (ATF4) levels were increased, confirming activation of the UPR in the gut of obese subjects. Furthermore, levels of both proteins correlated with BMI. Involvement of the UPR in the lowered antimicrobial protein levels in obese subjects was strongly suggested by a negative correlation between BiP levels and lysozyme levels. Additionally, indications of ER stress were apparent in Paneth cells of obese subjects. Our findings provide the first evidence for altered Paneth cell function in obesity, which may have important implications for the obesity-associated shift in microbiota composition. In addition, we show activation of the UPR in the intestine of obese subjects, which may underlie the observed Paneth cell compromise. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.