Title
Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles
Author
Martínez-Arranz, I.
Bruzzone, C.
Noureddin, M.
Gil-Redondo, R.
Mincholé, I.
Bizkarguenaga, M.
Arretxe, E.
Iruarrizaga-Lejarreta, M.
Fernández-Ramos, D.
Lopitz-Otsoa, F.
Mayo, R.
Embade, N.
Newberry, E.
Mittendorf, B.
Izquierdo-Sánchez, L.
Smid, V.
Arnold, J.
Iruzubieta, P.
Pérez Castaño, Y.
Krawczyk, M.
Marigorta, U.M.
Morrison, M.C.
Kleemann, R.
Martín-Duce, A.
Hayardeny, L.
Vitek, L.
Bruha, R.
Aller de la Fuente, R.
Crespo, J.
Romero-Gomez, M.
Banales, J.M.
Arrese, M.
Cusi, K.
Bugianesi, E.
Klein, S.
Lu, S.C.
Anstee, Q.M.
Millet, O.
Davidson, N.O.
Alonso, C.
Mato, J.M.
Publication year
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. © 2022 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.
To reference this document use:
http://resolver.tudelft.nl/uuid:366128ed-f4b8-4857-854e-e720f7c6f78f
DOI
https://doi.org/10.1002/hep.32427
TNO identifier
970606
Source
Hepatology, 76 (76), 121-134
Document type
article