Metabolomics analysis and modeling suggest a lysophosphocholines-PAF receptor interaction in fibromyalgia

Abstract

Fibromyalgia Syndrome (FMS) is a chronic disease characterized by widespread pain, and difficult to diagnose and treat. We analyzed the plasma metabolic profile of patients with FMS by using a metabolomics approach combining Liquid Chromatography-Quadrupole-Time Of Flight/Mass Spectrometry (LC-Q-TOF/MS) with multivariate statistical analysis, aiming to discriminate patients and controls. LC-Q-TOF/MS analysis of plasma (FMS patients: n = 22 and controls: n = 21) identified many lipid compounds, mainly lysophosphocholines (lysoPCs), phosphocholines and ceramides. Multivariate statistical analysis was performed to identify the discriminating metabolites. A protein docking and molecular dynamic (MD) study was then performed, using the most discriminating lysoPCs, to validate the binding to Platelet Activating Factor (1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, PAF) Receptor (PAFr). Discriminating metabolites between FMS patients and controls were identified as 1-tetradecanoyl-sn-glycero-3-phosphocholine [PC(14:0/0:0)] and 1-hexadecanoyl-sn-glycero-3-phosphocholine [PC(16:0/0:0)]. MD and docking indicate that the ligands investigated have similar potentialities to activate the PAFr receptor. The application of a metabolomic approach discriminated FMS patients from controls, with an over-representation of PC(14:0/0:0) and PC(16:0/0:0) compounds in the metabolic profiles. These results and the modeling of metabolite-PAFr interaction, allowed us to hypothesize that lipids oxidative fragmentation might generate lysoPCs in abundance, that in turn will act as PAF-like bioactivators. Overall results suggest disease biomarkers and potential therapeutical targets for FMS.

Figure 1. PCA (A) and PLS-DA (B) of plasma analysis from patients with FMS vs controls.

PLSA-DA values were: R²X = 0,345 R²Y = 0.901 Q² = 0,806 p-value = 1.1×10−12.

Figure 2. Contribution plot of plasma analysis from patients with FMS vs controls.

Figure 3. Best binding pose obtained for the ligands (i) PC(14∶0/0∶0) in green and (ii) PC(16∶0/0∶0) in red inside PAF receptor.

The receptor is shown using cartoon representation with helix 3 in pink and helix 6 in orange. The ligands are shown using ball and stick representation.