Journal article 592 views 132 downloads
Elevated oxysterol levels in human and mouse livers reflect nonalcoholic steatohepatitis
,
Marco Bueter,
Andreas Geier,
Gerhard Rogler,
Yuqin Wang,
Benjamin Misselwitz
Journal of Lipid Research, Volume: 60, Issue: 7, Pages: 1270 - 1283
Swansea University Author:
William Griffiths
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DOI (Published version): 10.1194/jlr.M093229
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-dihydro...
| Published in: | Journal of Lipid Research |
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| ISSN: | 0022-2275 1539-7262 |
| Published: |
2019
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa50635 |
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| 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. |
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| Keywords: |
nonalcoholic fatty liver disease, Epstein- Barr virus-induced gene 2, cholesterol 25 hydroxylase, 25-hydroxycholesterol 7 hydroxylase, mouse feeding model |
| Issue: |
7 |
| Start Page: |
1270 |
| End Page: |
1283 |