Abstract
Rheumatoid arthritis (RA) is significantly associated with glycolysis. This study used 2-deoxy-D-glucose (2-DG), an inhibitor of glycolysis, to treat rats with collagen-induced arthritis (CIA) and investigate the metabolic regulatory mechanism of glycolysis in the disease. 2-DG significantly alleviated CIA. Metabolomics and transcriptomics, as well as their integrative analysis, detected significant changes in the pathways of bile secretion, cholesterol and linoleic acid metabolism in the plasma, liver and spleen during the CIA process and the opposite changes following 2-DG treatment, whereas the expression of the genes regulating these metabolic pathways were changed only in the spleen. In the rat liver, levels of (S)-5-diphosphomevalonic acid in the terpenoid backbone biosynthesis pathway were significantly decreased during CIA progression and increased following 2-DG treatment, and levels of taurochenodeoxycholic acid in the pentose and glucuronate interconversions pathway showed the opposite results. In the spleen, levels of 3-methoxy-4-hydroxyphenylglycol glucuronide in bile secretion and 12(S)-leukotriene B4 in arachidonic acid metabolism were significantly decreased during CIA progression and increased following 2-DG treatment. The changes in the gene-metabolite network of bile secretion in the spleen correlated with a decreased plasma L-acetylcarnitine level in CIA rats and an increase following 2-DG treatment. Our analysis suggests the involvement of spleen and liver metabolism in CIA under the control of glycolysis.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis
The analysis indicated that differentially expressed metabolites (DEMs) between the healthy rats (P-H) and collagen-induced arthritis (CIA) rats (P-C) were closely related to antifolate resistance (p=0.0014) and regulation of lipolysis in adipocytes (p= 0.00095), among which all DEM levels were significantly increased in CIA rats; bile secretion (p
The analysis indicated that DEMs between CIA rats (P-C) and CIA rats treated with 2-DG (P-T) were closely related to amoebiasis (p=0.00048), bile secretion (p=0.00017), cholesterol metabolism (p
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory polyarthritis. Breakdown of self-tolerance and onset of autoimmunity are the main features of the disease. Many studies have detected increased glycolysis in RA synovial fluids and Glycolysis Regulation in Rheumatoid Arthritis inflammatory joints in a rat model of collagen-induced arthritis (CIA) [3,4,5]. The balance of glycolysis and oxidative phosphorylation is shifted toward glycolysis in RA fibroblast-like synoviocytes (FLSs) [6]. Glycolytic enzymes such as hexokinase 2 (HK2), phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB) and phosphoglycerate kinase (PGK) play essential roles in aggressive FLSs [3, 7]. Induction of glycolysis was critical for antibody production, as glycolytic inhibition with the pyruvate dehydrogenase kinase inhibitor dichloroacetate substantially suppressed B cell proliferation and antibody secretion in vitro and in vivo [13]. No study has combined metabolomics and transcriptomics to fully investigate the metabolic regulatory pathways of glycolysis in RA, and an integrative analysis combining metabolomic and transcriptomic data has not been conducted
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