Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis [Research Articles]

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-hydroxycho...

Source: The Journal of Lipid Research - June 30, 2019 Category: Lipidology Authors: Raselli, T., Hearn, T., Wyss, A., Atrott, K., Peter, A., Frey-Wagner, I., Spalinger, M. R., Maggio, E. M., Sailer, A. W., Schmitt, J., Schreiner, P., Moncsek, A., Mertens, J., Scharl, M., Griffiths, W. J., Bueter, M., Geier, A., Rogler, G., Wang, Y., Miss Tags: Research Articles Source Type: research