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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.

We examined the genotype-phenotype interactions of Cyp51+/− mice carrying one functional allele of lanosterol 14α-demethylase from cholesterol biosynthesis. No distinct developmental or morphological abnormalities were observed by routine visual inspection of Cyp51+/− and Cyp51+/+ mice and fertility was similar. We further collected a large data-set from female and male Cyp51+/− mice and controls fed for 16 weeks with three diets and applied linear regression modeling. We used 3 predictor variables (genotype, sex, diet), and 39 response variables corresponding to the organ characteristics (7), plasma parameters (7), and hepatic gene expression (25). We observed significant differences between Cyp51+/− and wild-type mice in organ characteristics and blood lipid profile. Hepatomegaly was observed in Cyp51+/− males, together with elevated total and low-density lipoprotein cholesterol. Cyp51+/− females fed high-fat, high-cholesterol diet were leaner and had elevated plasma corticosterone compared to controls. We observed elevated hepatocyte apoptosis, mitosis and lipid infiltration in heterozygous knockouts of both sexes. The Cyp51+/− females had a modified lipid storage homeostasis protecting them from weight-gain when fed high-fat high-cholesterol diet. Malfunction of one Cyp51 allele therefore initiates disease pathways towards cholesterol-linked liver pathologies and sex-dependent response to dietary challenge. [ABSTRACT FROM AUTHOR]