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Genome-scale metabo...
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Sen, Partho,1983-Örebro universitet,Institutionen för medicinska vetenskaper,Region Örebro län,Turku Bioscience, University of Turku, Systems Medicine Group, Turku, Finland
(author)
Genome-scale metabolic modeling of human hepatocytes reveals dysregulation of glycosphingolipid pathways in progressive non-alcoholic fatty liver disease
- Article/chapterEnglish2021
Publisher, publication year, extent ...
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Elsevier,2021
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LIBRIS-ID:oai:DiVA.org:oru-93394
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https://urn.kb.se/resolve?urn=urn:nbn:se:oru:diva-93394URI
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Language:English
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Summary in:English
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Subject category:vet swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Background and aims: Non-alcoholic fatty liver disease (NAFLD) is a spectrum of chronic liver diseases intertwined with the metabolic disorders. The prevalence of NAFLD is rapidly increasing worldwide, while the pathologyand the underlying mechanism driving NAFLD is not fully understood. In NAFLD, a series of metabolic changes takes place in the liver. However, the alteration of the metabolic pathways in the human liver along the progression of NAFLD,i.e., transition from non-alcoholic steatosis (NAFL) to steatohepatitis (NASH) through cirrhosis remains to be discovered. Here, we sought to examine the metabolic pathways of the human liver across the full histological spectrum of NAFLD.Method: We analyzed the whole liver tissue transcriptomic (RNA-Seq)1 and serum metabolomics data obtained from a large cohort of histologically characterized patients derived from the European NAFLD Registry (n = 206), and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. The integrative approach employed in this study has enabled us to understand the regulation of the metabolic pathways of human liver in NAFL, and with progressive NASH-associated fibrosis (F0-F4).Results: Our study 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, by applying genome-scale metabolic modeling, we were able to identify the metabolic differences among carriers of widely validated genetic variants associated with NAFLD/NASH disease severity in three genes (PNPLA3,TM6SF2andHSD17B13).Conclusion: The study provides insights into the underlying pathways of the progressive-fibrosing steatohepatitis. Of note, there is a marked dysregulation of the glycosphingolipid metabolism in the liver of the patients with advanced fibrosis.
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Govaere, OlivierTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
(author)
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Sinioja, Tim,1983-Örebro universitet,Institutionen för naturvetenskap och teknik,Department of Chemistry(Swepub:oru)tmsa
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McGlinchey, Aidan J,1984-Örebro universitet,Institutionen för medicinska vetenskaper(Swepub:oru)anmy
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Geng, DaweiDepartment of Chemistry, Örebro University, Örebro, Sweden
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Ratziu, VladAssistance Publique-Hôpitaux de Paris, hôpital Beaujon, University Paris-Diderot, Paris, France
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Bugianesi, ElisabettaDepartment of Medical Sciences, Division of Gastro-Hepatology, Turin, Italy
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Schattenberg, JoernMetabolic Liver Research Programm, Department of Medicine, University Hospital Mainz, Mainz, Germany
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Vidal-Puig, AntonioUniversity of Cambridge Metabolic Research Laboratories, Wellcome-MRC Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom
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Allison, MichaelLiver Unit, Department of Medicine, Cambridge Biomedical Research Centre, Cambridge University NHS FoundationTrust, Cambridge, United Kingdom
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Cockell, SimonNewcastle University, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle, United Kingdom
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Daly, Ann K.Newcastle University, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle, United Kingdom
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Hyötyläinen, Tuulia,1971-Örebro universitet,Institutionen för naturvetenskap och teknik,Department of Chemistry(Swepub:oru)tihn
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Anstee, QuentinTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, United Kingdom
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Oresic, Matej,1967-Örebro universitet,Institutionen för medicinska vetenskaper,Turku Bioscience, University of Turku, Systems Medicine Group, Turku, Finland(Swepub:oru)moc
(author)
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Örebro universitetInstitutionen för medicinska vetenskaper
(creator_code:org_t)
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In:Journal of Hepatology: Elsevier75:Suppl. 2, s. S256-S2560168-82781600-0641
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Govaere, Olivier
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Bugianesi, Elisa ...
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