Hydroxysteroid (17β) Dehydrogenase 7 Activity Is Essential for Fetal de Novo Cholesterol Synthesis and for Neuroectodermal Survival and Cardiovascular Differentiation in Early Mouse Embryos

Abstract

Hydroxysteroid (17beta) dehydrogenase 7 (HSD17B7) has been shown to catalyze the conversion of both estrone to estradiol (17-ketosteroid reductase activity) and zymosterone to zymosterol (3-ketosteroid reductase activity involved in cholesterol biosynthesis) in vitro. To define the metabolic role of the enzyme in vivo, we generated knockout mice deficient in the enzyme activity (HSD17B7KO). The data showed that the lack of HSD17B7 results in a blockage in the de novo cholesterol biosynthesis in mouse embryos in vivo, and HSD17BKO embryos die at embryonic day (E) 10.5. Analysis of neural structures revealed a defect in the development of hemispheres of the front brain with an increased apoptosis in the neuronal tissues. Morphological defects in the cardiovascular system were also observed from E9.5 onward. Mesodermal, endodermal, and hematopoietic cells were all detected by the histological analysis of the visceral yolk sac, whereas no organized vessels were observed in the knockout yolk sac. Immunohistological staining for platelet endothelial cell adhesion molecule-1 indicated that the complexity of the vasculature also was reduced in the HSD17B7KO embryos, particularly in the head capillary plexus and branchial arches. At E8.5-9.5, the heart development and the looping of the heart appeared to be normal in the HSD17B7KO embryos. However, at E10.5 the heart was dilated, and the thickness of the cardiac muscle and pericardium in the HSD17B7KO embryos was markedly reduced, and immunohistochemical staining for GATA-4 revealed that HSD17B7KO embryos had a reduced number of myocardial cells. The septum of the atrium was also defected in the knockout mice.

Mouse Knockout of the Cholesterogenic Cytochrome P450 Lanosterol 14α-Demethylase (Cyp51) Resembles Antley-Bixler Syndrome

“…There are four engineered knockouts of genes later in the pathway. Ablation of hydroxysteroid (17-␤)-dehydrogenase 7 (Hsd17b7) results in embryonic lethality at E10.5 (42,43). Early lethality of Hsd17b7 knock-out could be explained by its additional role in estradiol synthesis.…”

Malformation syndromes caused by disorders of cholesterol synthesis

“…Bottero et al ( 316 ), in a report of 2 new cases and review of the literature of 20 cases from 15 unrelated famitwo groups have generated targeted mutations in the mouse ( 304,305 ). Similar to the moderate Nsdhl defi cient Bpa 8H allele, homozygous null Hsd17b7 embryos for both targeted alleles die at ~E10.5 with very similar phenotypes, including pericardial effusion, vascular defects in the embryo and yolk sac, and malformations and delayed development of the brain.…”

Novel Targets for the Transcription Factors MEF2 in MA-10 Leydig Cells1

“…In MEF2-depleted MA-10 Leydig cells, expression of Hsd17b7, which encodes an enzyme essential for cholesterol synthesis [55,56], was reduced. This would suggest a role for MEF2 in cholesterogenesis in addition to steroidogenesis in Leydig cells.…”