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Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis / 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 Griffiths, Marco Bueter, Andreas Geier, Gerhard Rogler, Yuqin Wang, Benjamin Misselwitz
Journal of Lipid Research, Volume: 60, Issue: 7, Pages: 1270 - 1283
Swansea University Author: William Griffiths
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Non-alcoholic 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 7α,25-dihydro...
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Non-alcoholic 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 7α,25-dihydroxycholesterol (7α,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 livers of NASH patients by liquid chromatography-mass spectrometry and tested the role of the EBI2-7α,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 to 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-/- animals and animals with defects in the 7α,25-diHC synthesizing enzymes CH25H and CYP7B1 compared to wildtype 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 enhanced level of 7α- hydroxycholest-4-en-3-one, and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.
nonalcoholic fatty liver disease, Epstein- Barr virus-induced gene 2, cholesterol 25 hydroxylase, 25-hydroxycholesterol 7 hydroxylase, mouse feeding model