Hidden disease susceptibility and sexual dimorphism in the heterozygous knockout of Cyp51 from cholesterol synthesis
Research output: Contribution to journal › Journal article › Research › peer-review
We examined the genotype-phenotype interactions of Cyp51+/2 mice carrying one functional allele of lanosterol 14ademethylase from cholesterol biosynthesis. No distinct developmental or morphological abnormalities were observed by routine visual inspection of Cyp51+/2 and Cyp51+/+ mice and fertility was similar. We further collected a large data-set from female and male Cyp51+/2 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+/2 and wildtype mice in organ characteristics and blood lipid profile. Hepatomegaly was observed in Cyp51+/2 males, together with elevated total and low-density lipoprotein cholesterol. Cyp51+/2 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+/2 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.
Original language | English |
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Article number | e112787 |
Journal | PLoS ONE |
Volume | 9 |
Issue number | 11 |
ISSN | 1932-6203 |
DOIs | |
Publication status | Published - 13 Nov 2014 |
Externally published | Yes |
ID: 244570767