Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles

Ibon Martínez-Arranz, Chiara Bruzzone, Mazen Noureddin, Ruben Gil-Redondo, Itziar Mincholé, Maider Bizkarguenaga, Enara Arretxe, Marta Iruarrizaga-Lejarreta, David Fernández-Ramos, Fernando Lopitz-Otsoa, Rebeca Mayo, Nieves Embade, Elizabeth Newberry, Bettina Mittendorf, Laura Izquierdo-Sánchez, Vaclav Smid, Jorge Arnold, Paula Iruzubieta, Ylenia Pérez Castaño, Marcin KrawczykUrko M. Marigorta, Martine C. Morrison, Robert Kleemann, Antonio Martín-Duce, Liat Hayardeny, Libor Vitek, Radan Bruha, Rocío Aller de la Fuente, Javier Crespo, Manuel Romero-Gomez, Jesus M. Banales, Marco Arrese, Kenneth Cusi, Elisabetta Bugianesi, Samuel Klein, Shelly C. Lu, Quentin M. Anstee, Oscar Millet, Nicholas O. Davidson, Cristina Alonso, José M. Mato

Research output: Contribution to journalArticlepeer-review

29 Scopus citations


Background and Aims: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. Approach and 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. The percent of patients with NASH and fibrosis was 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 with subtypes B and C. Subtype A VLDL-TG and VLDL–apolipoprotein 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 with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 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 versus cardiovascular outcomes, offering clinically relevant risk stratification.

Original languageEnglish
Pages (from-to)1121-1134
Number of pages14
Issue number4
StatePublished - Oct 2022


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