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2015 ; 11
(5
): 1157-1174
Nephropedia Template TP
gab.com Text
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Comprehensive metabolome analyses reveal N-acetylcysteine-responsive accumulation
of kynurenine in systemic lupus erythematosus: implications for activation of the
mechanistic target of rapamycin
#MMPMID26366134
Perl A
; Hanczko R
; Lai ZW
; Oaks Z
; Kelly R
; Borsuk R
; Asara JM
; Phillips PE
Metabolomics
2015[]; 11
(5
): 1157-1174
PMID26366134
show ga
Systemic lupus erythematosus (SLE) patients exhibit depletion of the
intracellular antioxidant glutathione and downstream activation of the metabolic
sensor, mechanistic target of rapamycin (mTOR). Since reversal of glutathione
depletion by the amino acid precursor, N-acetylcysteine (NAC), is therapeutic in
SLE, its mechanism of impact on the metabolome was examined within the context of
a double-blind placebo-controlled trial. Quantitative metabolome profiling of
peripheral blood lymphocytes (PBL) was performed in 36 SLE patients and 42
healthy controls matched for age, gender, and ethnicity of patients using mass
spectrometry that covers all major metabolic pathways. mTOR activity was assessed
by western blot and flow cytometry. Metabolome changes in lupus PBL affected 27
of 80 KEGG pathways at FDR p < 0.05 with most prominent impact on the pentose
phosphate pathway (PPP). While cysteine was depleted, cystine, kynurenine,
cytosine, and dCTP were the most increased metabolites. Area under the receiver
operating characteristic curve (AUC) logistic regression approach identified
kynurenine (AUC = 0.859), dCTP (AUC = 0.762), and methionine sulfoxide
(AUC = 0.708), as top predictors of SLE. Kynurenine was the top predictor of NAC
effect in SLE (AUC = 0.851). NAC treatment significantly reduced kynurenine
levels relative to placebo in vivo (raw p = 2.8 × 10(-7), FDR corrected
p = 6.6 × 10(-5)). Kynurenine stimulated mTOR activity in healthy control PBL in
vitro. Metabolome changes in lupus PBL reveal a dominant impact on the PPP that
reflect greater demand for nucleotides and oxidative stress. The PPP-connected
and NAC-responsive accumulation of kynurenine and its stimulation of mTOR are
identified as novel metabolic checkpoints in lupus pathogenesis.