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Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
Zitieren Sie bitte immer diese URN: urn:nbn:de:bvb:20-opus-225004
- Nonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers ofNonalcoholic steatohepatitis (NASH), a primary cause of liver disease, leads to complications such as fibrosis, cirrhosis, and carcinoma, but the pathophysiology of NASH is incompletely understood. Epstein-Barr virus-induced G protein-coupled receptor 2 (EBI2) and its oxysterol ligand 7 alpha,25-dihydroxycholesterol (7 alpha,25-diHC) are recently discovered immune regulators. Several lines of evidence suggest a role of oxysterols in NASH pathogenesis, but rigorous testing has not been performed. We measured oxysterol levels in the livers of NASH patients by LC-MS and tested the role of the EBI2-7 alpha,25-diHC system in a murine feeding model of NASH. Free oxysterol profiling in livers from NASH patients revealed a pronounced increase in 24- and 7-hydroxylated oxysterols in NASH compared with controls. Levels of 24- and 7-hydroxylated oxysterols correlated with histological NASH activity. Histological analysis of murine liver samples demonstrated ballooning and liver inflammation. No significant genotype-related differences were observed in Ebi2(-/-) mice and mice with defects in the 7 alpha,25-diHC synthesizing enzymes CH25H and CYP7B1 compared with wild-type littermate controls, arguing against an essential role of these genes in NASH pathogenesis. Elevated 24- and 7-hydroxylated oxysterol levels were confirmed in murine NASH liver samples. Our results suggest increased bile acid synthesis in NASH samples, as judged by the enhanced level of 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.…
Autor(en): | Tina Raselli, Tom Hearn, Annika Wyss, Kirstin Atrott, Alain Peter, Isabelle Frey-Wagner, Marianne R. Spalinger, Ewerton M. Maggio, Andreas W. Sailer, Johannes Schmitt, Philipp Schreiner, Anja Moncsek, Joachim Mertens, Michael Scharl, William J. Griffiths, Marco Bueter, Andreas Geier, Gerhard Rogler, Yuqin Wang, Benjamin Misselwitz |
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URN: | urn:nbn:de:bvb:20-opus-225004 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Medizinische Klinik und Poliklinik II |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | Journal of Lipid Research |
Erscheinungsjahr: | 2019 |
Band / Jahrgang: | 60 |
Heft / Ausgabe: | 7 |
Seitenangabe: | 1270-1283 |
Originalveröffentlichung / Quelle: | Journal of Lipid Research, Volume 60, 2019, 1270-1283 |
DOI: | https://doi.org/10.1194/jlr.M093229 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | 25-hydroxycholesterol 7 alpha-hydroxylase; Epstein-Barr virus-induced gene 2; cholesterol 25 hydroxylase; mouse feeding model; nonalcoholic fatty liver disease |
Datum der Freischaltung: | 11.01.2022 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International |