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Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles

Lookup NU author(s): Dr Paula Iruzubieta, Professor Quentin AnsteeORCiD

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Abstract

© 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. 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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Author(s): Martinez-Arranz I, Bruzzone C, Noureddin M, Gil-Redondo R, Minchole I, Bizkarguenaga M, Arretxe E, Iruarrizaga-Lejarreta M, Fernandez-Ramos D, Lopitz-Otsoa F, Mayo R, Embade N, Newberry E, Mittendorf B, Izquierdo-Sanchez L, Smid V, Arnold J, Iruzubieta P, Perez Castano Y, Krawczyk M, Marigorta UM, Morrison MC, Kleemann R, Martin-Duce A, Hayardeny L, Vitek L, Bruha R, Aller de la Fuente R, Crespo J, Romero-Gomez M, Banales JM, Arrese M, Cusi K, Bugianesi E, Klein S, Lu SC, Anstee QM, Millet O, Davidson NO, Alonso C, Mato JM

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2022

Volume: 76

Issue: 4

Pages: 1121-1134

Print publication date: 01/10/2022

Online publication date: 26/02/2022

Acceptance date: 15/02/2022

Date deposited: 29/03/2022

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley and Sons Inc.

URL: https://doi.org/10.1002/hep.32427

DOI: 10.1002/hep.32427

PubMed id: 35220605

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