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Energy Metabolism Disorder as a Contributing Factor of Rheumatoid Arthritis: A Comparative Proteomic and Metabolomic Study.

Yang XY, Zheng KD, Lin K, Zheng G, Zou H, Wang JM, Lin YY, Chuka CM, Ge RS, Zhai W, Wang JG - PLoS ONE (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

ABSTRACT

Objectives: To explore the pathogenesis of rheumatoid arthritis (RA), the different metabolites were screened in synovial fluid by metabolomics.

Methods: 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.

Results: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus

Energy metabolism profiles obtained from RA patients and normal subjects based on comparative proteomics and metabolomics study.The different metabolites and enzymes are marked with a rectangle and a circle, respectively. The number means the ratio of RA to normal. Arrow means the direction of reaction.
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pone.0132695.g004: Energy metabolism profiles obtained from RA patients and normal subjects based on comparative proteomics and metabolomics study.The different metabolites and enzymes are marked with a rectangle and a circle, respectively. The number means the ratio of RA to normal. Arrow means the direction of reaction.

Mentions: Rheumatoid arthritis is an autoimmune disease involving multiple molecules and pathways. Given the integrated nature of systemic metabolism may provide a better understanding of the disease-associated changes [23,24]. Glucose metabolism not only provides energy for physical activity but also mediates a variety of physiological processes through the formation of complex signaling networks. Cells need energy supplied by ATP, which is mainly produced by the anaerobic decomposition and aerobic oxidation pathways [16,25]. Maximum aerobic oxidation of glucose per molecule can generate 32 ATP molecules. Anaerobic decomposition can produce two ATP molecules [11], which is significantly lower than the number of ATP molecules produced by aerobic oxidation [12]. Then, what is the main energy metabolism in RA joints? An overview of the present metabolomic study and our previous proteomic result indicates the possibility of clarifying the exact mechanism underlying the observed perturbation between RA patients and healthy controls, and revealing the energy metabolism of RA (Fig 4).


Energy Metabolism Disorder as a Contributing Factor of Rheumatoid Arthritis: A Comparative Proteomic and Metabolomic Study.

Yang XY, Zheng KD, Lin K, Zheng G, Zou H, Wang JM, Lin YY, Chuka CM, Ge RS, Zhai W, Wang JG - PLoS ONE (2015)

Energy metabolism profiles obtained from RA patients and normal subjects based on comparative proteomics and metabolomics study.The different metabolites and enzymes are marked with a rectangle and a circle, respectively. The number means the ratio of RA to normal. Arrow means the direction of reaction.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492520&req=5

pone.0132695.g004: Energy metabolism profiles obtained from RA patients and normal subjects based on comparative proteomics and metabolomics study.The different metabolites and enzymes are marked with a rectangle and a circle, respectively. The number means the ratio of RA to normal. Arrow means the direction of reaction.
Mentions: Rheumatoid arthritis is an autoimmune disease involving multiple molecules and pathways. Given the integrated nature of systemic metabolism may provide a better understanding of the disease-associated changes [23,24]. Glucose metabolism not only provides energy for physical activity but also mediates a variety of physiological processes through the formation of complex signaling networks. Cells need energy supplied by ATP, which is mainly produced by the anaerobic decomposition and aerobic oxidation pathways [16,25]. Maximum aerobic oxidation of glucose per molecule can generate 32 ATP molecules. Anaerobic decomposition can produce two ATP molecules [11], which is significantly lower than the number of ATP molecules produced by aerobic oxidation [12]. Then, what is the main energy metabolism in RA joints? An overview of the present metabolomic study and our previous proteomic result indicates the possibility of clarifying the exact mechanism underlying the observed perturbation between RA patients and healthy controls, and revealing the energy metabolism of RA (Fig 4).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China.

ABSTRACT

Objectives: To explore the pathogenesis of rheumatoid arthritis (RA), the different metabolites were screened in synovial fluid by metabolomics.

Methods: 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.

Results: 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.

Conclusion: 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.

No MeSH data available.


Related in: MedlinePlus