Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling
| Autor: | Rolf Gebhardt, Dan R. Littman, Martina Perše, Ingemar Björkhem, Gregor Lorbek, Damjana Rozman, Peter Juvan, Jason A. Hall, Richard Bonneau, Žiga Urlep, Madlen Matz-Soja, Jera Jeruc |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male medicine.medical_specialty Article 03 medical and health sciences chemistry.chemical_compound Mice RAR-related orphan receptor gamma Internal medicine medicine Animals Regulation of gene expression Liver injury Mice Knockout Sex Characteristics Multidisciplinary Fatty acid metabolism Lanosterol Gene Expression Profiling Liver Diseases Runt Nuclear Receptor Subfamily 1 Group F Member 3 medicine.disease Fibrosis Disease Models Animal Sterols 030104 developmental biology Endocrinology medicine.anatomical_structure Cholesterol chemistry Gene Expression Regulation Hepatocyte Knockout mouse Cytochrome P450 Family 51 Disease Progression Hepatocytes Unfolded Protein Response Female Signal Transduction |
| Zdroj: | Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | Development of mice with hepatocyte knockout of lanosterol 14α-demethylase (HCyp51−/−) 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 HCyp51−/− 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. |
| Databáze: | OpenAIRE |
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