Direct Remnant Lipoprotein Profiling Reveals Subfraction-Level Associations with Biopsy-Proven MASH in Severe Obesity

AIMS: Directly measured remnant cholesterol (RC) has been linked to hepatic histological activity, but subfraction associations with metabolic dysfunction-associated steatohepatitis (MASH) in severe obesity remain unclear. We examined these associations, compared direct markers with estimated RC, and assessed added information beyond clinical variables. METHODS: This cross-sectional study included 380 adults with severe obesity undergoing bariatric surgery; 110 had MASH. Vertical Auto Profile (VAP) quantified remnant subfractions. Multivariable logistic regression assessed associations. Incremental information was assessed by the area under the receiver operating characteristic curve (AUC), continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI). An exploratory four-variable model was bootstrap-validated. RESULTS: Measured RC was independently associated with MASH (fully adjusted odds ratio [OR] per standard deviation, 1.32; 95% confidence interval [CI], 1.05-1.67), whereas estimated RC was not. Among direct subfractions, very-low-density lipoprotein 3 cholesterol (VLDL3-C) showed the most consistent association (OR, 1.36; 95% CI, 1.08-1.70; P < 0.01), whereas intermediate-density lipoprotein cholesterol was significant only after fuller adjustment. All three direct markers produced similarly modest gains in discrimination, NRI, and IDI, with no clear differences in head-to-head comparisons. VLDL3-C was therefore selected for an exploratory four-variable model based on its consistent association and favorable model fit, achieving an optimism-corrected AUC of 0.724. At the lower cutoff, 34.5% of participants were classified as low risk, with 90.0% sensitivity and a negative predictive value of 91.6%. CONCLUSION: VAP profiling links remnant-related cholesterol to MASH at the subfraction level. VLDL3-C warrants further evaluation for risk assessment.