Metabolic Disturbances Associated with Systemic Lupus Erythematosus

Abstract

The metabolic disturbances that underlie systemic lupus erythematosus are currently unknown. A metabolomic study was executed, comparing the sera of 20 SLE patients against that of healthy controls, using LC/MS and GC/MS platforms. Validation of key differences was performed using an independent cohort of 38 SLE patients and orthogonal assays. SLE sera showed evidence of profoundly dampened glycolysis, Krebs cycle, fatty acid β oxidation and amino acid metabolism, alluding to reduced energy biogenesis from all sources. Whereas long-chain fatty acids, including the n3 and n6 essential fatty acids, were significantly reduced, medium chain fatty acids and serum free fatty acids were elevated. The SLE metabolome exhibited profound lipid peroxidation, reflective of oxidative damage. Deficiencies were noted in the cellular anti-oxidant, glutathione, and all methyl group donors, including cysteine, methionine, and choline, as well as phosphocholines. The best discriminators of SLE included elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE. Importantly, similar elevations were not observed in another chronic inflammatory autoimmune disease, rheumatoid arthritis. To sum, comprehensive profiling of the SLE metabolome reveals evidence of heightened oxidative stress, inflammation, reduced energy generation, altered lipid profiles and a pro-thrombotic state. Resetting the SLE metabolome, either by targeting selected molecules or by supplementing the diet with essential fatty acids, vitamins and methyl group donors offers novel opportunities for disease modulation in this disabling systemic autoimmune ailment.

Lactate at the crossroads of metabolism, inflammation, and autoimmunity

“…In contrast, a metabolomics study on SLE sera revealed reduced glycolysis, Krebs cycle, fatty acid β oxidation, and aa metabolism in these patients compared to healthy controls. This dysregulation associates with dampened energy generation, high oxidative stress, inflammation, altered lipid profiles, and a prothrombotic state [69]. Furthermore, serum levels of total LDH, LDH1, and LDH2 were significantly higher in patients with diffuse proliferative lupus nephritis and showed good correlations with the activity index and the total pathologic score of the renal pathologic scoring system, and with the glomerular hypercellularity.…”

Application of metabolomics in autoimmune diseases: Insight into biomarkers and pathology

“…LC/MS and GC/MS platforms were used to compare metabolite profiling in the serum between SLE patients and healthy controls. The SLE patients presented elevated lipid peroxidation products, MDA, gamma-glutamyl peptides, GGT, leukotriene B4 and 5-HETE, which indicated lipid peroxidation and oxidative damage (Wu et al, 2012). Using NMR spectrums accompanied with the PCA and OPLS-DA models, the SLE serum samples were characterized by decreased concentrations of valine, tyrosine, phenylalanine, lysine, isoleucine, histidine, glutamine, alanine, citrate, creatinine, creatine, pyruvate, high-density lipoprotein, cholesterol, glycerol, formate and increased concentrations of N-acetyl glycoprotein, very low-density lipoprotein and low-density lipoprotein (Ouyang et al, 2011).…”

Metabolic control of the epigenome in systemic Lupus erythematosus

“…SLE lymphocytes have hypomethylated DNA and increased oxidative stress due to the depletion of GSH [17,27,49]. This may be due to the accumulation of SAH from blockage in the SAM pathway that prevents recycling of SAH and homocysteine to methionine or cystathionine.…”