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GNPS - Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment

ABSTRACT: Background Currently, it is not possible to predict whether patients with hyperuricemia (HUA) will develop gout and how this progression may be affected by urate-lowering treatment (ULT). Our study aimed to evaluate differences in plasma lipidome between patients with asymptomatic HUA detected < 40 years (HUA<40) and > 40 years, gout patients with disease onset < 40 years (Gout<40) and > 40 years, and normouricemic healthy controls (HC). Methods Plasma samples were collected from 94 asymptomatic HUA (77% HUA<40) subjects, 196 gout patients (59% Gout<40), and 53 HC. A comprehensive targeted lipidomic analysis was performed to semi-quantify 608 lipids in plasma. Univariate and multivariate statistics and advanced visualizations were applied. Results Both HUA and gout patients showed alterations in lipid profiles with the most significant upregulation of phosphatidylethanolamines and downregulation of lysophosphatidylcholine plasmalogens/plasmanyls. More profound changes were observed in HUA<40 and Gout<40 without ULT. Multivariate statistics differentiated HUA<40 and Gout<40 groups from HC with an overall accuracy of > 95%. Conclusion Alterations in the lipidome of HUA and Gout patients show a significant impact on lipid metabolism. The most significant glycerophospholipid dysregulation was found in HUA<40 and Gout<40 patients, together with a correction of this imbalance with ULT. Keywords LC-MS, Lipidomics, Glycerophospholipids, Hyperuricemia, Gout, Urate-lowering treatment Study was published and is accessible under this DOI: https://doi.org/10.1186/s13075-023-03204-6 Please cite as follows: Kvasni?ka, A., Friedecký, D., Brumarová, R. et al. Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment. Arthritis Res Ther 25, 234 (2023). https://doi.org/10.1186/s13075-023-03204-6

INSTRUMENT(S): ExionLC, QTRAP 6500+

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Blanka Stiburkova

PROVIDER: MSV000093082 | GNPS | Wed Oct 11 07:02:00 BST 2023

REPOSITORIES: GNPS

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Project description:A need exists for biomarkers in T1D that can 1) sensitively and specifically detect disease-related immune activity prior to, and independent of, measurement of auto-antibodies towards islet cell antigens; 2) define immunopathological mechanisms; and 3) monitor changes in the inflammatory state associated with disease progression or response to therapeutic intervention. In an effort to fill this gap, we have applied a novel bioassay to both human and BB rat T1D whereby the complex milieu of inflammatory mediators present in plasma can be indirectly detected through their ability to drive transcription in peripheral blood mononuclear cells (PBMCs) drawn from healthy, unrelated donors. The resultant gene expressions are comprehensively measured with a microarray. In our human studies, we find that plasma of recent-onset T1D patients induces expression of a pro-inflammatory signature consisting in part of many interleukin-1 (IL-1) regulated genes related to immunological activation and immunocyte chemotaxis compared to unrelated healthy controls. This signature has been found to resolve in long-standing T1D subjects (>10 years post-onset), thus associating it with active autoimmunity. Importantly, this signature has been detected in pre-onset samples of progressors to T1D years prior to onset and prior to development of auto-antibodies directed towards islet antigens. In applying this approach to the BN rat, we observed that samples collected from both sub-strains at 60 days of age induced transcription of genes encoding cytokines, immune receptors, and signaling molecules consistent with a their shared susceptibility and immune activation. The DRlyp/lyp signature was differentiated from that of the DR+/+ by more robust induction of many interleukin (IL)-1M-bM-^@M-^Sregulated genes. Treatment of DRlyp/lyp rats with IL-1 receptor antagonist (IL-1RN) delayed onset and, in part, normalized the signature, suggesting that this approach may prove useful in monitoring the effect of therapeutic interventions in human T1D. Consistent with the presence of TREG cells in DR+/+ rats, we observed induction of a signature possessing negative regulators of transcription and inflammation. Fresh PBMCs of healthy Brown Norway (BN) rats (~180 days old males, to avoid variation introduced by estrous or pubertal status) were isolated by density gradient centrifugation. Transcription was induced by culturing PBMCs for 6 h at 37M-BM-0C in 5% CO2 with 20% allogeneic BN (healthy-unrelated control), DRlyp/lyp, or DR+/+ plasma [PMID 18209091]. DRlyp/lyp and DR+/+ Plasma was pooled at various ages (30, 40, 50, 60 days old) to represent timepoints prior to onset in the DRlyp/lyp strain.

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GNPS - Alterations in lipidome profiles distinguish early-onset hyperuricemia, gout, and the effect of urate-lowering treatment

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