title: Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling.
abstract: 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.
authors.affiliation: Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Urlep
authors.affiliation: Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Gregor
authors.initials: G
authors.lastname: Lorbek
authors.affiliation: Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Martina
authors.initials: M
authors.lastname: Perše
authors.affiliation: Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Jera
authors.initials: J
authors.lastname: Jeruc
authors.affiliation: Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Peter
authors.initials: P
authors.lastname: Juvan
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Madlen
authors.initials: M
authors.lastname: Matz-Soja
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska Institute, Karolinska University Hospital, Huddinge, Sweden.
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Hall
authors.affiliation: New York University &Simons Foundation for Data Analysis, New York, NY 10010, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Bonneau
authors.affiliation: The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, New York 10016, USA.|Howard Hughes Medical Institute, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Dan R
authors.initials: DR
authors.lastname: Littman
authors.affiliation: Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000096:biosynthesis*; D000072505:Cytochrome P450 Family 51 / Q000235:genetics*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005355:Fibrosis; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism*; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D012727:Sex Characteristics; D015398:Signal Transduction; D013261:Sterols / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539901:Rorc protein, mouse; D013261:Sterols; D002784:Cholesterol; D000072505:Cytochrome P450 Family 51