Oxidative and endoplasmic reticulum stress is impaired in leukocytes from metabolically unhealthy vs healthy obese individuals
Oxidative and endoplasmic reticulum stress is impaired in leukocytes from metabolically unhealthy vs healthy obese individuals
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DOI：
10.1038/ijo.2017.147
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发表时间：
2017-10-01
影响因子：
4.9
通讯作者：
Hernandez-Mijares, A.
中科院分区：
文献类型：
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作者：
Banuls, C.;Rovira-Llopis, S.;Hernandez-Mijares, A.
背景：氧化应激和炎症与肥胖有关，但代谢紊乱对这些参数的影响及其与内质网应激的关系尚不清楚。因此，本研究旨在评估代谢谱是否会影响有/无合并症的肥胖人群的内质网和氧化应激。研究对象和方法：共纳入113例肥胖患者；29例代谢健康（MHO）， 53例代谢异常（MAO）， 31例2型糖尿病（MADO）。我们评估了代谢参数、促炎因子（TNF α和IL-6）、线粒体和总活性氧（ROS）产生、谷胱甘肽水平、抗氧化酶活性、总抗氧化状态、线粒体膜电位和内质网应激标志物(葡萄糖调节蛋白（GRP78）、剪接X-box结合蛋白1 （XBP1）、p -亚基1 α （P-eIF2 α)和激活转录因子6 (ATF6)）的表达水平。结果：MAO组和MADO组的血压、动脉粥样硬化性血脂异常、胰岛素抵抗和炎症状况均高于MHO组。MAO组和MHO组总ROS和线粒体ROS生成增强，线粒体膜电位和过氧化氢酶活性在MADO组和MHO组之间存在显著差异。此外，与MAO和MHO组相比，mdo组的谷胱甘肽水平和超氧化物歧化酶活性均有所下降。与MHO受试者相比，MAO和MADO组GRP78和CHOP蛋白及基因表达较高，sXBP1基因表达与糖尿病存在相关。此外，MAO患者比MHO患者表现出更高的ATF6水平。腰围与ATF6、GRP78呈正相关，A1c与P-Eif2 α呈正相关。有趣的是，CHOP与TNF α和总ROS生成呈正相关，GRP78与谷胱甘肽水平负相关。结论：我们的研究结果支持了炎症和氧化应激都参与了代谢不健康肥胖与健康肥胖受试者白细胞内质网应激信号通路的诱导的假设。
BACKGROUND: Oxidative stress and inflammation are related to obesity, but the influence of metabolic disturbances on these parameters and their relationship with endoplasmic reticulum (ER) stress is unknown. Therefore, this study was performed to evaluate whether metabolic profile influences ER and oxidative stress in an obese population with/without comorbidities.SUBJECTS AND METHODS: A total of 113 obese patients were enrolled in the study; 29 were metabolically healthy (MHO), 53 were metabolically abnormal (MAO) and 31 had type 2 diabetes (MADO). We assessed metabolic parameters, proinflammatory cytokines (TNF alpha and IL-6), mitochondrial and total reactive oxygen species (ROS) production, glutathione levels, antioxidant enzymes activity, total antioxidant status, mitochondrial membrane potential and ER stress marker expression levels (glucose-regulated protein (GRP78), spliced X-box binding protein 1 (XBP1), P-subunit 1 alpha (P-eIF2 alpha) and activating transcription factor 6 (ATF6).RESULTS: The MAO and MADO groups showed higher blood pressure, atherogenic dyslipidemia, insulin resistance and inflammatory profile than that of MHO subjects. Total and mitochondrial ROS production was enhanced in MAO and MADO patients, and mitochondrial membrane potential and catalase activity differed significantly between the MADO and MHO groups. In addition, decreases in glutathione levels and superoxide dismutase activity were observed in the MADO vs MAO and MHO groups. GRP78 and CHOP protein and gene expression were higher in the MAO and MADO groups with respect to MHO subjects, and sXBP1 gene expression was associated with the presence of diabetes. Furthermore, MAO patients exhibited higher levels of ATF6 than their MHO counterparts. Waist circumference was positively correlated with ATF6 and GRP78, and A1c was positively correlated with P-Eif2 alpha. Interestingly, CHOP was positively correlated with TNF alpha and total ROS production and GRP78 was negatively correlated with glutathione levels.CONCLUSIONS: Our findings support the hypothesis that both inflammation and oxidative stress are involved in the induction of ER stress signaling pathways in the leukocytes of metabolically unhealthy obese vs healthy obese subjects.