Energy Metabolism Disorder as a Contributing Factor of Rheumatoid Arthritis: A Comparative Proteomic and Metabolomic Study.
Energy Metabolism Disorder as a Contributing Factor of Rheumatoid Arthritis: A Comparative Proteomic and Metabolomic Study.
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能量代谢紊乱是类风湿关节炎的一个促成因素：比较蛋白质组学和代谢组学研究
DOI：
10.1371/journal.pone.0132695
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wang JG
中科院分区：
文献类型：
--
作者：
Yang XY;Zheng KD;Lin K;Zheng G;Zou H;Wang JM;Lin YY;Chuka CM;Ge RS;Zhai W;Wang JG
为探讨类风湿关节炎（RA）的发病机制，应用代谢组学方法筛选RA患者关节液中的代谢产物。本文采用GC/TOF MS法对25例RA患者和10例正常人的关节液进行了分析，从而对关节液代谢产物进行了全面的概述。采用多元统计分析比较RA患者和正常人的代谢特征。通过qPCR和蛋白质印迹验证不同的蛋白质。用比色法检测25例非活动期RA患者、25例活动期RA患者和20例正常人的代谢产物。采用基因敲低法检测缺氧诱导因子（HIF）-1α通路对细胞增殖的影响。确定了58种代谢物的子集，其中与能量代谢相关的7种代谢物的浓度显著不同，如投影（VIP）（VIP≥1）和Student t检验（p<0.05）中的重要性所示。在7种代谢产物中，RA患者滑液中葡萄糖浓度较正常人降低，乳酸浓度较正常人升高，并经比色法检测证实。受试者工作特征（ROC）分析表明，滑液中葡萄糖和乳酸的浓度可以作为诊断活动性RA的可靠生物标志物，AUC分别为0.906和0.922。以临界点为标准，敏感性和特异性分别为84%和96%，特异性分别为95%和85%。对我们前期蛋白质组学研究中鉴定的不同蛋白质的验证表明，RA患者厌氧代谢酶（PFKP和LDHA）表达上调，有氧氧化和脂肪酸氧化酶（CS、DLST、PGD、ACSL 4、ACADVL和HADHA）表达下调。FLS细胞中HIF-1α表达下调，有氧氧化酶和脂肪酸氧化酶表达下调，无氧代谢酶表达上调。研究发现，缺氧诱导因子调节的无氧代谢增强和有氧氧化减少是RA发生发展的新因素，关节液中低血糖和高乳酸浓度可能是RA的潜在生物标志物。
To explore the pathogenesis of rheumatoid arthritis (RA), the different metabolites were screened in synovial fluid by metabolomics. Synovial fluid from 25 RA patients and 10 normal subjects were analyzed by GC/TOF MS analysis so as to give a broad overview of synovial fluid metabolites. The metabolic profiles of RA patients and normal subjects were compared using multivariate statistical analysis. Different proteins were verified by qPCR and western blot. Different metabolites were verified by colorimetric assay kit in 25 inactive RA patients, 25 active RA patients and 20 normal subjects. The influence of hypoxia-inducible factor (HIF)-1α pathway on catabolism was detected by HIF-1α knockdown. A subset of 58 metabolites was identified, in which the concentrations of 7 metabolites related to energy metabolism were significantly different as shown by importance in the projection (VIP) (VIP≥1) and Student’s t-test (p<0.05). In the 7 metabolites, the concentration of glucose was decreased, and the concentration of lactic acid was increased in the synovial fluid of RA patients than normal subjects verified by colorimetric assay Kit. Receiver operator characteristic (ROC) analysis shows that the concentration of glucose and lactic acid in synovial fluid could be used as dependable biomarkers for the diagnosis of active RA, provided an AUC of 0.906 and 0.922. Sensitivity and specificity, which were determined by cut-off points, reached 84% and 96% in sensitivity and 95% and 85% in specificity, respectively. The verification of different proteins identified in our previous proteomic study shows that the enzymes of anaerobic catabolism were up-regulated (PFKP and LDHA), and the enzymes of aerobic oxidation and fatty acid oxidation were down-regulated (CS, DLST, PGD, ACSL4, ACADVL and HADHA) in RA patients. The expression of HIF-1α and the enzymes of aerobic oxidation and fatty acid oxidation were decreased and the enzymes of anaerobic catabolism were increased in FLS cells after HIF-1α knockdown. It was found that enhanced anaerobic catabolism and reduced aerobic oxidation regulated by HIF pathway are newly recognized factors contributing to the progression of RA, and low glucose and high lactic acid concentration in synovial fluid may be the potential biomarker of RA.
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影响因子：
64.8
作者：
Sreekumar, Arun;Poisson, Laila M.;Rajendiran, Thekkelnaycke M.;Khan, Amjad P.;Cao, Qi;Yu, Jindan;Laxman, Bharathi;Mehra, Rohit;Lonigro, Robert J.;Li, Yong;Nyati, Mukesh K.;Ahsan, Aarif;Kalyana-Sundaram, Shanker;Han, Bo;Cao, Xuhong;Byun, Jaeman;Omenn, Gilbert S.;Ghosh, Debashis;Pennathur, Subramaniam;Alexander, Danny C.;Berger, Alvin;Shuster, Jeffrey R.;Wei, John T.;Varambally, Sooryanarayana;Beecher, Christopher;Chinnaiyan, Arul M.
通讯作者：
Chinnaiyan, Arul M.
影响因子：
3.7
作者：
Kim S;Hwang J;Xuan J;Jung YH;Cha HS;Kim KH
通讯作者：
Kim KH
影响因子：
4.9
作者：
Giatromanolaki, A;Sivridis, E;Koukourakis, MI
通讯作者：
Koukourakis, MI
影响因子：
4.9
作者：
Spies CM;Straub RH;Buttgereit F
通讯作者：
Buttgereit F
影响因子：
--
作者：
Kapoor, Sabrina R.;Filer, Andrew;Fitzpatrick, Martin A.;Fisher, Benjamin A.;Taylor, Peter C.;Buckley, Christopher D.;McInnes, Iain B.;Raza, Karim;Young, Stephen P.
通讯作者：
Young, Stephen P.