CYP17A1 deficient XY mice display susceptibility to atherosclerosis, altered lipidomic profile and atypical sex development

Redouane Aherrahrou,Ralf Werner,Jeanette Erdmann,Heribert Schunkert,Zouhair Aherrahrou,Simeon Vens-Cappell,Michael Bader,Natalia Alenina,Alexandra E Kulle

doi:10.1038/s41598-020-65601-0

Abstract

CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. CYP17A1 genetic variants are associated with coronary artery disease, myocardial infarction and visceral and subcutaneous fat distribution; however, the underlying pathological mechanisms remain unknown. We aimed to investigate the function of CYP17A1 and its impact on atherosclerosis in mice. At 4–6 months, CYP17A1-deficient mice were viable, with a KO:Het:WT ratio approximating the expected Mendelian ratio of 1:2:1. All Cyp17a1 knockout (KO) mice were phenotypically female; however, 58% were Y chromosome-positive, resembling the phenotype of human CYP17A1 deficiency, leading to 46,XY differences/disorders of sex development (DSD). Both male and female homozygous KO mice were infertile, due to abnormal genital organs. Plasma steroid analyses revealed a complete lack of testosterone in XY-KO mice and marked accumulation of progesterone in XX-KO mice. Elevated corticosterone levels were observed in both XY and XX KO mice. In addition, Cyp17a1 heterozygous mice were also backcrossed onto an Apoe KO atherogenic background and fed a western-type diet (WTD) to study the effects of CYP17A1 on atherosclerosis. Cyp17a1 x Apoe double KO XY mice developed more atherosclerotic lesions than Apoe KO male controls, regardless of diet (standard or WTD). Increased atherosclerosis in CYP17A1 XY KO mice lacking testosterone was associated with altered lipid profiles. In mice, CYP17A1 deficiency interferes with sex differentiation. Our data also demonstrate its key role in lipidomic profile, and as a risk factor in the pathogenesis of atherosclerosis.

Highlights

CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities
Inheritance plays an essential role in the pathogenesis of Coronary artery disease (CAD), and recent genome-wide association studies (GWAS) have revealed more than 160 genomic loci associated with this condition[2]
After the generation of Cyp17a1 KO mice and confirmation of KO by PCR analysis at genomic DNA level (Fig. 1a,b), qPCR analysis at RNA level (Supplemental Fig. 2d) and immunhistostaining at protein level (Supplemental Figs. 1c,d and 2a,b), mice were initially characterized in our laboratory at 4–6 months old

Summary

Introduction

CYP17A1 is a cytochrome P450 enzyme with 17-alpha-hydroxylase and C17,20-lyase activities. All Cyp17a1 knockout (KO) mice were phenotypically female; 58% were Y chromosome-positive, resembling the phenotype of human CYP17A1 deficiency, leading to 46,XY differences/disorders of sex development (DSD). Increased atherosclerosis in CYP17A1 XY KO mice lacking testosterone was associated with altered lipid profiles. The same locus is associated with myocardial infarction (MI)[3] and visceral and subcutaneous fat distribution[4] This locus harbors the CYP17A1 gene, which encodes the cytochrome P450 17A1 enzyme, referred to as steroid 17-alpha-monooxygenase or 17α-hydroxylase/17,20-lyase/17,20-desmolase. In addition to adrenal steroid biosynthesis CYP17A1-deficiency affects gonadal steroid biosynthesis manifesting as disorders/differences of sex development (DSDs), leading to female or ambiguous external genitalia in 46,XY individuals and lack of pubertal development in boys and girls[8,9]. Castration of Apoe knockout male mice led to increase atherosclerosis[20]

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