Georgiana Cabău (1), Marko Barovic (2), HINT-consortium, Triantafyllos Chavakis (2), Tania O. Crișan (1), and Leo Joosten (1,3)
Affiliation(s):
1. Department of Medical Genetics, “Iuliu Haţieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania
2. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, Dresden, Germany
3. Department of Internal Medicine, Radboudumc, Nijmegen, the Netherlands
Background & Objectives: Gout and asymptomatic hyperuricemia (AH) are characterized by both metabolic dysregulation and systemic inflammation, yet the interplay between lipid alterations and inflammatory responses remains insufficiently understood. Nuclear magnetic resonance (NMR)-based metabolomics enables the characterization of metabolite and lipid species, providing insights into metabolic disturbances associated with these conditions. While dyslipidaemia, including elevated very-low-density lipoprotein (VLDL), has been previously reported in gout and AH, its relationship with inflammatory pathways remains unclear.
This study aims to: (i) identify metabolomic and lipidomic alterations distinguishing gout and AH from normouricemic controls; (ii) investigate correlations between these metabolic shifts and in vivo inflammatory responses; and (iii) explore potential mechanistic links in vitro through peripheral blood mononuclear cell (PBMC) stimulations.
Methods: Serum samples from patients with gout, AH, and normouricemic controls were analyzed using an NMR-targeted metabolomics approach to profile lipid and metabolic alterations. Principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were employed to identify key metabolites differentiating groups, while correlation analyses with inflammatory serum proteins provided insights into lipid-associated immune activation.
Results: Preliminary analyses reveal a distinct lipidomic profile in gout and AH, characterized by alterations in multiple lipid species, including VLDL-related fractions and other lipoprotein-associated metabolites. These metabolic changes show correlations with inflammatory serum proteins, suggesting a potential interaction between dyslipidemia and immune activation.
Conclusions & Significance: This study integrates targeted metabolomics and proteomics to examine metabolic-inflammatory interactions in gout and AH. By integrating NMR-based metabolic profiling with inflammatory protein signatures in vivo and further functional immune responses in vitro, we demonstrate that dyslipidemia may play a role in immune activation, potentially informing metabolic and immunomodulatory therapeutic strategies.
Future studies will extend these findings by conducting in vitro PBMC stimulations with soluble urate and Toll-like receptor (TLR) ligands to assess cytokine production (IL-1β, IL-1Ra, IL-6) in relation to observed lipidomic alterations. Additionally, VLDL stimulations will be explored to determine its inflammatory potential, providing mechanistic insights into its contribution to systemic inflammation in gout and AH. These ongoing investigations aim to determine whether targeting lipid alterations could offer novel avenues for reducing inflammation in hyperuricemic conditions.