Hidden disease susceptibility and sexual dimorphism in the heterozygous knockout of Cyp51 from cholesterol synthesis.
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.
Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
Monika
M
Lewinska
Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
Peter
P
Juvan
Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
Martina
M
Perse
Medical Experimental Centre, Institute of Pathology, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
Jera
J
Jeruc
Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia; Institute of Oncology Ljubljana, Zaloška cesta 2, SI-1000, Ljubljana, Slovenia.
Spela
S
Kos
Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
Gregor
G
Lorbek
Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
Ziga
Z
Urlep
Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230, Domžale, Slovenia.
Rok
R
Keber
Department of Animal Science, Biotechnical Faculty, University of Ljubljana, Groblje 3, 1230, Domžale, Slovenia; National Institute of Chemistry, Hajdrihova 19, 1000, Ljubljana, Slovenia.
Simon
S
Horvat
Center for Functional Genomics and Bio-Chips, Faculty of Medicine, University of Ljubljana, SI-1000, Ljubljana, Slovenia.
Damjana
D
Rozman
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002784:Cholesterol / Q000096:biosynthesis / Q000235:genetics; D004041:Dietary Fats / Q000009:adverse effects / Q000494:pharmacology; D005260:Female; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006529:Hepatomegaly / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D006579:Heterozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000187:drug effects / Q000235:genetics; D012727:Sex Characteristics; D058886:Sterol 14-Demethylase / Q000235:genetics / Q000378:metabolism
D004041:Dietary Fats; D002784:Cholesterol; C548415:Cyp51 protein, mouse; D058886:Sterol 14-Demethylase