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Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease
Örebro University, School of Medical Sciences.ORCID iD: 0000-0001-6682-6030
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Department of Chemistry, Örebro University, Örebro, Sweden.ORCID iD: 0000-0002-8553-8824
Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, University Paris-Diderot, Paris, France.
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2022 (English)In: JHEP Reports, E-ISSN 2589-5559, Vol. 4, no 5, article id 100477Article in journal (Refereed) Published
Abstract [en]

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis).

Methods: We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis.

Results: Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered.

Conclusions: Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2-F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress.

Clinical Trials registration: The study is registered at Clinicaltrials.gov (NCT04442334).

Lay summary: Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic 'watershed' in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases.

Place, publisher, year, edition, pages
Elsevier, 2022. Vol. 4, no 5, article id 100477
Keywords [en]
Fibrosis, Lipidomics, Mass spectrometry, Metabolomics, Non-alcoholic steatohepatitis
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-98643DOI: 10.1016/j.jhepr.2022.100477ISI: 000795853800009PubMedID: 35434590Scopus ID: 2-s2.0-85127766899OAI: oai:DiVA.org:oru-98643DiVA, id: diva2:1653299
Funder
EU, Horizon 2020
Note

Funding agencies:

Elucidating Pathways of Steatohepatitis (EPoS) consortium - Horizon 2020634413

Innovative Medicines Initiative (IMI2) Program of the European Union 777377

EFPIA

Newcastle NIHR Biomedical Research Centre

European NAFLD Registry

Available from: 2022-04-21 Created: 2022-04-21 Last updated: 2024-06-24Bibliographically approved

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McGlinchey, Aidan JHyötyläinen, TuuliaOresic, Matej

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