Role of activity and fibrosis in the MASLD atherogenic momentum through advanced lipidomics

Introduction MASLD is linked to dyslipidemia, but it remains unclear whether this alteration depends more on disease activity or fibrosis. Objective To determine whether dyslipidemia is primarily associated with activity and/or fibrosis through standard lipid profile and advanced lipidomics. Methods A cross-sectional study was conducted including patients with suspected MASLD at a single center. Intraoperative liver biopsies were obtained. Only patients with MASLD were included in the analysis. Histological activity was defined as a NAFLD Activity Score (NAS) ≥5 and fibrosis was staged according to standard criteria. Clinical, biochemical, lipoprotein, and fatty acid profiles were assessed, including nuclear magnetic resonance (NMR) spectroscopy for lipoprotein subfractions and gas chromatography for fatty acids. Multivariable linear regression models were used to evaluate independent associations of activity and fibrosis with lipid parameters. Results A total of 49 patients were analyzed (mean age 48 years, 46% men, 94% with BMI > 35). Liver biopsies revealed a 30.6% prevalence of activity (NAS ≥ 5) and 36.7% of fibrosis. Higher lipid levels in patients with activity were related to apolipoprotein B, non-HDL cholesterol, and triglycerides in both univariate and multivariate models. Fibrosis was not associated with any lipid parameter. Lipidomics confirmed associations of activity with VLDL+IDL cholesterol (β = 0.474, 95% CI 0.204–0.745, p = 0.001), VLDL+IDL triglycerides (β = 0.454, 95% CI 0.198–0.710, p = 0.001), and VLDL particle concentration (β = 0.409, 95% CI 0.155–0.663, p = 0.002), and showed a trend toward an inverse association with the percentage of large VLDL particles (β=−0.298, 95% CI −0.602–0.006, p = 0.054). Besides, the omega-6/triglycerides ratio was inversely associated with activity (β=−0.345, 95% CI −0.630 to −0.060, p = 0.019). Conclusion Hepatic inflammatory activity showed strong associations with a non-traditional atherogenic lipidomic profile. These findings suggest that activity, rather than liver fibrosis, may be a key factor in the MASLD atherosclerotic momentum.