Author/Editor		Lewinska, Monika; Juvan, Peter; Perše, Martina; Jeruc, Jera; Kos, Špela; Lorbek, Gregor; Urlep, Žiga; Keber, Rok; Horvat, Simon; Rozman, Damjana
Title		Hidden disease susceptibility and sexual dimorphism in the heterozygous knockout of Cyp51 from cholesterol synthesis
Type		članek
Vol. and No.		Letnik 9, št. 11
Publication year		2014
ISSN		1932-6203 - PloS one
Language		eng
Abstract		We examined the genotype-phenotype interactions of Cyp51+/- mice carrying one functional allele of lanosterol 14alpha-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.
Keywords		cholesterol synthesis sexual dimorphism biosynthesis sinteza holesterola spolni dimorfizem biosinteza