Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles
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Date
2022-10Author
Martínez Arranz, Ibon
Bruzzone, Chiara
Noureddin, Mazen
Gil Redondo, Rubén
Mincholé, Itziar
Bizkarguenaga, Maider
Arretxe Oliden, Enara
Iruarrizaga Lejarreta, Marta
Fernández Ramos, David
Lopitz Otsoa, Fernando
Mayo, Rebeca
Embade, Nieves
Newberry, Elizabeth
Mittendorf, Bettina
Izquierdo Sánchez, Laura
Smid, Vaclav
Arnold, Jorge
Iruzubieta, Paula
Pérez Castaño, Ylenia
Krawczyk, Marcin
Morrison, Martine C.
Kleemann, Robert
Martín Duce, Antonio
Hayardeny, Liat
Vitek, Libor
Bruha, Radan
Aller de la Fuente, Rocio
Crespo, Javier
Romero Gómez, Manuel
Arrese, Marco
Cusi, Kenneth
Bugianesi, Elisabetta
Klein, Samuel
Lu, Shelly C.
Anstee, Quentin M.
Millet Aguilar-Galindo, Oscar
Davidson, Nicholas O.
Alonso, Cristina
Mato, José M.
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Hepatology 76(4) : 1121-1134 (2022)
Abstract
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.
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