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Cited by 65Liver Disease Diagnosis and TreatmentDiabetes, Cardiovascular Risks, and LipoproteinsMetabolomics and Mass Spectrometry Studies

Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles

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Martínez‐Arranz, Ibon, Bruzzone, Chiara, Noureddin, Mazen, Gil‐Redondo, Ruben, Mincholé, Itziar, Bizkarguenaga, Maider, Arretxe, Enara, Iruarrizaga‐Lejarreta, Marta +33 more·2022·Hepatology
DOI 10.1002/hep.32427PMC PMC9790568
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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 LDL 5,6, 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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  • Metabolomic studies indicate that roughly 50% of persons with MASLD exhibit a phenotype characteristic of reduced VLDL secretion.

    “Importantly, metabolomic studies also indicate that roughly 50% of persons with MASLD exhibit a phenotype characteristic of reduced VLDL secretion (18).”

    From Loss of function of T-box 3 in the liver protects against MASLD (2025) · cites this paper as [18]

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Authors
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.
Affiliations
  • OWL (Spain) (ES)
  • CIC bioGUNE (ES)
  • Cedars-Sinai Medical Center (US)
  • CIC bioGUNE,BRTA,CIBERehd,Derio,Bizkaia,Spain
  • Washington University in St. Louis (US)
  • Biogipuzkoa Health Research Institute (ES)
  • Charles University (CZ)
  • Pontificia Universidad Católica de Chile (CL)
  • Universidad de Cantabria (ES)
  • Department of Digestive System,Osakidetza Basque Health Service,Donostia University Hospital,San Sebastian,Spain
  • Medical University of Warsaw (PL)
  • Netherlands Organisation for Applied Scientific Research (NL)
  • Alcalá University School of Medicine and Health Sciences,University Hospital Prıncipe de Asturias,Madrid,Spain
  • Galmed Pharmaceuticals (Israel) (IL)
  • First Faculty of Medicine,Charles University,Prague,Czech Republic
  • Department of Digestive Disease,Clinic University Hospital,University Hospital of Valladolid,Valladolid,Spain
  • Valme University Hospital,CiBERehd,Sevilla,Spain
  • Department of Liver and Gastrointestinal Diseases,Biodonostia Research Institute,Donostia University Hospital,Donostia,Spain
  • University of Florida (US)
  • University of Turin (IT)
  • NIHR Newcastle Biomedical Research Centre (GB)
Corresponding author
  • Alonso, Cristina
  • Mato, José M.
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2022-03-17
Volume
76
Issue
4
Pages
1121-1134
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.32427
PMC
PMC9790568
OpenAlex
W4214496831
Cited by
65
References
10
Citations by year
2026: 12 · 2025: 7 · 2024: 20 · 2023: 18 · 2022: 8
FWCI
9.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
  • TNO Repository (submittedVersion)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by-nc)
  • Communities in ADDI (University of the Basque Country) (submittedVersion, cc-by-nc)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
  • Hispana (submittedVersion, cc-by-nc)
  • UCrea (University of Cantabria) (submittedVersion, cc-by-nc)
  • Newcastle University ePrints (Newcastle Univesity) (cc-by-nc)
Funders
  • Abbott Laboratories
  • Eli Lilly and Company
  • Pfizer
  • AstraZeneca
  • GlaxoSmithKline
  • Gilead Sciences
  • Medpace
  • “la Caixa” Foundation (HR17-00601)
  • European Federation of Pharmaceutical Industries and Associations (777377)
  • Medicines Company
  • National Institute for Health and Care Research (777377)
  • European Commission (777377, HORIZON2020, 825510)
  • Ministerio de Economía y Competitividad (SEV-2016-0644), CON14/00129, SAF2017‐88041‐R)
  • Novo Nordisk
  • Ekonomiaren Garapen eta Lehiakortasun Saila, Eusko Jaurlaritza (KK‐2020/00008)
  • Shionogi
  • Agentura Pro Zdravotnický Výzkum České Republiky (RVO‐VFN64165/2020)
  • Servier
  • Fondo Nacional de Ciencia y Tecnología
  • Nederlandse Organisatie voor Toegepast Natuurwetenschappelijk Onderzoek (PMC13, PMC15)
  • Agencia Nacional de Investigación y Desarrollo (ANID ACE 210009, 210009, 825510, 1191145, AFB170005)
  • National Institutes of Health (HL151328, UL1TR002345)
  • Genentech
  • Allergan
  • Horizon 2020 Framework Programme (777377)
  • Comisión Nacional de Investigación Científica y Tecnológica (AFB-170005)
  • Instituto de Salud Carlos III (SEV-2016-0644, CON14/00129, PI18/01075, CPII19/00008, HR17-00601, 01132, PI15/01132, 01075)
  • European Regional Development Fund (SAF2017, CPII19/00008, CON14/00129, HR17-00601, 825510)
  • Centro de Envejecimiento y Regeneración, Pontificia Universidad Católica de Chile (825510, AFB170005, 1191145)
  • National Heart, Lung, and Blood Institute (P01HL151328)
  • National Institute of Diabetes and Digestive and Kidney Diseases (R01DK123763, P30DK056341, R01DK119437, P30DK052574)
  • National Center for Advancing Translational Sciences
  • Fondo Nacional de Desarrollo Científico y Tecnológico (1191145)
Topics
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Keywords
non-alcoholic fatty liver disease, metabolic subtypes, serum metabolome, cardiovascular risk, VLDL triglyceride secretion, apolipoprotein B, lipoprotein metabolism, NASH, liver fibrosis, genetic risk factors, risk stratification
MeSH terms
Heart Disease Risk Factors, Animals, Apolipoproteins B, Cardiovascular Diseases, Lipoproteins, VLDL, Liver, Phospholipases, Risk Factors, Triglycerides, Cholesterol, VLDL, Mice, Non-alcoholic Fatty Liver Disease

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