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Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease
Örebro University, School of Medical Sciences. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.ORCID iD: 0000-0003-0475-2763
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Örebro University, School of Science and Technology.
Örebro University, School of Medical Sciences.ORCID iD: 0000-0001-6682-6030
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2022 (English)In: iScience, E-ISSN 2589-0042 , Vol. 25, no 9, article id 104949Article in journal (Refereed) Published
Abstract [en]

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here, we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue transcriptomics and serum metabolomics data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants (PNPLA3, TM6SF2, and HSD17B13). The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.

Place, publisher, year, edition, pages
Cell Press , 2022. Vol. 25, no 9, article id 104949
Keywords [en]
Health sciences, Metabolomics, Omics, Systems biology
National Category
Gastroenterology and Hepatology
Identifiers
URN: urn:nbn:se:oru:diva-101123DOI: 10.1016/j.isci.2022.104949ISI: 000861134500001PubMedID: 36065182Scopus ID: 2-s2.0-85136475793OAI: oai:DiVA.org:oru-101123DiVA, id: diva2:1693503
Funder
European CommissionNovo Nordisk, NNF20OC0063971Academy of Finland
Note

Funding agencies:

EPOS (Elucidating Pathways of Steatohepatitis) - Horizon 2020 Framework Program of the European Union 634413

Innovative Medicines Initiative 2 Joint Undertaking 777377

EFPIA

UK Research & Innovation (UKRI)

Medical Research Council UK (MRC)

  

Available from: 2022-09-07 Created: 2022-09-07 Last updated: 2025-02-11Bibliographically approved

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Sen, ParthoSinioja, TimMcGlinchey, Aidan JHyötyläinen, TuuliaOresic, Matej

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