Hidden Disease Susceptibility and Sexual Dimorphism in the Heterozygous Knockout of Cyp51 from Cholesterol Synthesis

Abstract

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.

Evaluation of serum bone alkaline phosphatase activity in patients with liver disease: Comparison between electrophoresis and chemiluminescent enzyme immunoassay

“…TC in women was significantly higher than in men in our study. Previous research highlighted a difference between males and females in the causes of liver disease, with TC synthesis representing a key point of gender difference [27]. In addition, γ-GTP values of all samples were increased, with those in men significantly higher than those in women.…”

Disrupting Hepatocyte Cyp51 from Cholesterol Synthesis Leads to Progressive Liver Injury in the Developing Mouse and Decreases RORC Signalling

“…3) likely due to cholesterol compensation during the initial 3-week nursing period. The switch to standard laboratory chow lacking cholesterol27 raises the need for its endogenous synthesis. As this is disrupted in the knockout livers, the result is a fall in plasma and liver cholesterol at 6 weeks that is remedied at later ages, and alterations of sterol metabolites.…”

“…Cyp51 flox/flox ( Cyp51 +/+ ) and heterozygous Cyp51 -/flox ( Cyp51 +/− ) mice were used as controls27. Mice were euthanized at different time points during development – 0, 3, 6, 9 and 19 weeks.…”

Role of Protein-Protein Interactions in Metabolism: Genetics, Structure, Function

“…Heterozygous knockout Cyp51a1 +/− mice are developmentally and morphologically normal and fertile; however, when challenged with high lipid diet, the response revealed a hidden susceptibility to detrimental effects of the diet (Lewinska et al, 2014). Studies in mice also revealed gender biased consequences of mutations in Cyp51a1 (Lorbek et al, 2013;Lewinska et al, 2014;Urlep et al, 2017). Consequences of CYP51A1 heterozygosity in humans need yet to be studied.…”