Background/Purpose: This study aims to:1- Characterize the circulating metabolomic signature in APS patients; 2- Investigate the role of hepatic involvement in the pathophysiology of APS; 3- Evaluate the direct effects of aPLs on the metabolism of hepatic cells in vitro; 4- Examine the short-term impact of ubiquinol (reduced CoQ10) supplementation both in vivo and in vitro on the disrupted liver–metabolome axis.

Methods: Serum metabolomic profiling of 129 primary APS patients and 43 healthy donors (HDs) was performed using nuclear magnetic resonance (Nightingale), quantifying over 250 metabolites. Longitudinal changes were assessed in a subgroup of 15 APS patients who received ubiquinol supplementation for one month (clinical trial NCT02218476). The involvement of liver function was explored in vivo and in vitro. Correlations between circulating metabolites, liver-related biomarkers, and aPLs were carried out. In vitro, HepG2 cells were treated with purified aPLs, and their functional responses were assessed (Seahorse XF Palmitate Oxidation Stress Test Kit, WB, RT-PCR), both alone and in combination with CoQ10.

Results: Metabolomic profiling revealed 53 significantly altered metabolites in APS patients including decreased atheroprotective lipids (HDL-related lipids) and elevated pro-atherogenic mediators (VLDL, LDL). These alterations were associated with arterial thrombosis, atheroma plaques, and recurrent thrombotic events. Evidence for liver involvement was supported by significant correlations between circulating metabolites, liver transaminases, FIB-4 index, and aPL levels.In vitro studies reinforced the hypothesis of liver involvement. Exposure of HepG2 cells to purified aPLs increased the secretion of LDL and VLDL and upregulated hepatic injury markers. Functional metabolic assays demonstrated enhanced fatty acid oxidation under metabolic stress, accompanied by increased pACC1/ACC1 ratio and ACAA2 expression. This metabolic shift may promote triglyceride synthesis and facilitate the export of proatherogenic VLDL particles. Moreover, in APS patients, ubiquinol supplementation partially corrected the altered lipidomic profile by decreasing pro-atherogenic and increasing anti-atherogenic markers. In vitro, pre-treatment of hepatocytes with CoQ10 effectively prevented the liver alterations induced by aPLs exposure.

Conclusion: 1- APS patients display a distinct pro-atherogenic serum metabolomic profile2- Liver involvement in APS is supported by clinical correlations and in vitro evidence showing that aPL promote hepatocyte dysfunction, induce metabolic reprogramming and enhance atherogenic lipid export.3- Ubiquinol supplementation mitigates metabolic and hepatic disturbances in APS both in vivo and in vitro,These findings reveal a novel liver–metabolism–autoantibody axis in APS, which appears to be attenuated by ubiquinol supplementation.Fundings: ISCIII (PI24/00959, CD21/00187, RD24/0007/0019), co-financed by European Union-NextGeneration EU, via PRTR. RYC2021-033828-I. PID2022-141500OA-I00.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-a-new-pathogenic-axis-in-antiphospholipid-syndrome-linking-antiphospholipid-antibodies-liver-function-and-circulating-proatherogenic-metabolites/