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Elevated oxysterol levels in human and mouse livers reflect non-alcoholic steatohepatitis

Raselli, T and Heran, T and Wyss, A and Atrott, K and Peter, A and Frey-Wagner, I and Spalinger, MR and Maggio, EM and Sailer, Andreas and Schmitt, J and Schreiner, P and Wiest, R and Moncsek, A and Mertens, J and Scharl, M and Griffiths, WJ and Bueter, M and Geier , A and Rogler, G and Wang, Y and Misselwitz, B (2019) Elevated oxysterol levels in human and mouse livers reflect non-alcoholic steatohepatitis. JLR papers in press, 60. pp. 1270-1283. ISSN 1539-7262

Abstract

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.

Item Type: Article
Keywords: Bile acids and salts Cholesterol G proteins Liver Mass spectrometry Nutrition Obesity
Date Deposited: 24 Jul 2019 00:45
Last Modified: 24 Jul 2019 00:45
URI: https://oak.novartis.com/id/eprint/38959

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