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
Affiliations
Partho Sen
School of Medical Sciences, Örebro University, 70281 Örebro, Sweden; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland
Olivier Govaere
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Tim Sinioja
Department of Chemistry, Örebro University, 70281 Örebro, Sweden
Aidan McGlinchey
School of Medical Sciences, Örebro University, 70281 Örebro, Sweden
Dawei Geng
Department of Chemistry, Örebro University, 70281 Örebro, Sweden
Vlad Ratziu
Assistance Publique-Hôpitaux de Paris, hôpital Beaujon, University Paris-Diderot, Paris, France
Elisabetta Bugianesi
Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy
Jörn M. Schattenberg
Metabolic Liver Research Programm, Department of Medicine, University Hospital Mainz, Mainz, Germany
Antonio Vidal-Puig
University of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
Michael Allison
Liver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS Foundation Trust, UK
Simon Cockell
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Ann K. Daly
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
Tuulia Hyötyläinen
Department of Chemistry, Örebro University, 70281 Örebro, Sweden
Quentin M. Anstee
Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; Newcastle NIHR Biomedical Research Center, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Corresponding author
Matej Orešič
School of Medical Sciences, Örebro University, 70281 Örebro, Sweden; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; Corresponding author
Summary: 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.
