| Abstract: | BACKGROUND & AIMS: We previously identified subsets of NAFLD patients with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. APPROACH & RESULTS: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. Percent of patients with NASH and fibrosis were comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared to subtypes B and C. Subtype A VLDL-TG and VLDL-Apo-B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol, were lower among subtype A compared to subtypes B and C. The 10-year high-risk of CVD, measured with the Framingham risk score, and the frequency of PNPLA3 NAFLD risk allele were lower in subtype A. CONCLUSIONS: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic vs. cardiovascular outcomes, offering novel, clinically relevant, risk stratification. |
