Open AccessHidden Disease Susceptibility and Sexual Dimorphism in the Heterozygous Knockout of Cyp51 from Cholesterol Synthesis
Author(s) -
Monika Lewiñska,
Peter Juvan,
Martina Perše,
Jera Jeruc,
Špela Kos,
Gregor Lorbek,
Žiga Urlep,
Rok Keber,
Simon Horvat,
Damjana Rozman
Publication year - 2014
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0112787
Subject(s) - cholesterol , biology , medicine , endocrinology , sexual dimorphism , lanosterol , genotype , allele , high density lipoprotein , knockout mouse , lipoprotein , high cholesterol , sterol , genetics , gene
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.