Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease

Partho Sen; Olivier Govaere; Tim Sinioja; Aidan McGlinchey; Dawei Geng; Vlad Ratziu; Elisabetta Bugianesi; Jörn M Schattenberg; Antonio Vidal-Puig; Michael Allison; Simon Cockell; Ann K Daly; Tuulia Hyötyläinen; Quentin M Anstee; Matej Orešič

doi:10.1016/j.isci.2022.104949

Quantitative modeling of human liver reveals dysregulation of glycosphingolipid pathways in nonalcoholic fatty liver disease

iScience. 2022 Aug 15;25(9):104949. doi: 10.1016/j.isci.2022.104949. eCollection 2022 Sep 16.

Authors

Partho Sen^{1

2}, Olivier Govaere³, Tim Sinioja⁴, Aidan McGlinchey¹, Dawei Geng⁴, Vlad Ratziu⁵, Elisabetta Bugianesi⁶, Jörn M Schattenberg⁷, Antonio Vidal-Puig⁸, Michael Allison⁹, Simon Cockell³, Ann K Daly³, Tuulia Hyötyläinen⁴, Quentin M Anstee^{3

10}, Matej Orešič^{1

2}

Affiliations

¹ School of Medical Sciences, Örebro University, 70281 Örebro, Sweden.
² Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
³ Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
⁴ Department of Chemistry, Örebro University, 70281 Örebro, Sweden.
⁵ Assistance Publique-Hôpitaux de Paris, hôpital Beaujon, University Paris-Diderot, Paris, France.
⁶ Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy.
⁷ Metabolic Liver Research Programm, Department of Medicine, University Hospital Mainz, Mainz, Germany.
⁸ University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
⁹ Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, UK.
¹⁰ Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.

Abstract

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.

Keywords: Health sciences; Metabolomics; Omics; Systems biology.

Abstract

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