Journal
JOURNAL OF LIPID RESEARCH
Volume 60, Issue 7, Pages 1270-1283Publisher
ELSEVIER
DOI: 10.1194/jlr.M093229
Keywords
nonalcoholic fatty liver disease; Epstein-Barr virus-induced gene 2; cholesterol 25 hydroxylase; 25-hydroxycholesterol 7 alpha-hydroxylase; mouse feeding model
Categories
Funding
- Swiss National Science Foundation [32473B_156525]
- Hartmann-Muller Foundation
- UK Biotechnology and Biological Sciences Research Council [BB/L001942/1]
- AbbVie
- Ardeypharm
- MSD
- Falk
- Flamentera
- Novartis
- Roche
- Tillots
- UCB
- Zeller
- Exalenz (Liver Investigation: Testing Marker Utility in Steatohepatitis
- LITMUS)
- Intercept (Nonalcoholic Fatty Liver Disease Clinical Study Group
- NAFLD CSG)
- Kibion
- Swiss National Science Foundation (SNF) [32473B_156525] Funding Source: Swiss National Science Foundation (SNF)
- BBSRC [BB/L001942/1] Funding Source: UKRI
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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 7 alpha,25-dihydroxycholesterol (7 alpha,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 EBI2-7 alpha,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 7 alpha,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 7 alpha-hydroxycholest-4-en-3-one and impaired 24S-hydroxycholesterol metabolism as characteristic biochemical changes in livers affected by NASH.
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