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Elevated Oxysterol Levels in Human and Mouse Livers Reflect Nonalcoholic Steatohepatitis

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, etc.

J Lipid Res. 2019 Jul;60(7):1270-1283.

PMID: 31113816

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP64907228	7α,25-Dihydroxycholesterol		64907-22-8	Price

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