Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling

Development of mice with hepatocyte knockout of lanosterol 14α-demethylase (H Cyp51 −/− ) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout fem...

Full description

Saved in:
Bibliographic Details
Published in:Scientific reports 2017-01, Vol.7 (1), p.40775-40775, Article 40775
Main Authors: Urlep, Žiga, Lorbek, Gregor, Perše, Martina, Jeruc, Jera, Juvan, Peter, Matz-Soja, Madlen, Gebhardt, Rolf, Björkhem, Ingemar, Hall, Jason A., Bonneau, Richard, Littman, Dan R., Rozman, Damjana
Format: Article
Language:English
Subjects:
38
38/39
38/61
38/91
631/208/199
631/45/287/1197
64
64/110
692/4020/4021/1607
Amino acids
Cholesterol
Fibrosis
Gene regulation
Humanities and Social Sciences
Intermediates
Lanosterol
Liver diseases
Metabolism
multidisciplinary
Puberty
Rodents
Science
Science (multidisciplinary)
Sex differences
Transcription
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Development of mice with hepatocyte knockout of lanosterol 14α-demethylase (H Cyp51 −/− ) from cholesterol synthesis is characterized by the progressive onset of liver injury with ductular reaction and fibrosis. These changes begin during puberty and are generally more aggravated in the knockout females. However, a subgroup of (pre)pubertal knockout mice (runts) exhibits a pronounced male prevalent liver dysfunction characterized by downregulated amino acid metabolism and elevated Casp12. RORC transcriptional activity is diminished in livers of all runt mice, in correlation with the depletion of potential RORC ligands subsequent to CYP51 disruption. Further evidence for this comes from the global analysis that identified a crucial overlap between hepatic Cyp51 −/− and Rorc −/− expression profiles. Additionally, the reduction in RORA and RORC transcriptional activity was greater in adult H Cyp51 −/− females than males, which correlates well with their downregulated amino and fatty acid metabolism. Overall, we identify a global and sex-dependent transcriptional de-regulation due to the block in cholesterol synthesis during development of the Cyp51 knockout mice and provide in vivo evidence that sterol intermediates downstream of lanosterol may regulate the hepatic RORC activity.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep40775