Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis.

Raselli, Tina; Hearn, Tom; Wyss, Annika; Atrott, Kirstin; Peter, Alain; Frey-Wagner, Isabelle; Spalinger, Marianne R; Maggio, Ewerton M; Sailer, Andreas W; Schmitt, Johannes; Schreiner, Philipp; Moncsek, Anja; Mertens, Joachim; Scharl, Michael; Griffiths, William J; Bueter, Marco; Geier, Andreas; Rogler, Gerhard; Wang, Yuqin and Misselwitz, Benjamin (2019). Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis. Journal of lipid research, 60(7), pp. 1270-1283. American Society for Biochemistry and Molecular Biology ASBMB 10.1194/jlr.M093229

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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 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 the livers of NASH patients by LC-MS 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 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 7α,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 7α-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.

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