Hydroxysteroid (17β) Dehydrogenase 12 Is Essential for Mouse Organogenesis and Embryonic Survival

Abstract

Hydroxysteroid (17beta) dehydrogenases (HSD17Bs) have a significant role in steroid metabolism by catalyzing the conversion between 17-keto and 17beta-hydroxysteroids. However, several studies in vitro have shown that some of these enzymes may also be involved in other metabolic pathways. Among these enzymes, HSD17B12 has been shown to be involved in both the biosynthesis of estradiol and the elongation of the essential very long fatty acids in vitro and in vivo. To investigate the function of mammalian HSD17B12 in vivo, we generated mice with a null mutation of the Hsd17b12 gene (HSD17B12KO mice) by using a gene-trap vector, resulting in the expression of the lacZ gene of the trapped allele. The beta-galactosidase staining of the heterozygous HSD17B12KO mice revealed that Hsd17b12 is expressed widely in the embryonic day (E) 7.5-E9.5 embryos, with the highest expression in the neural tissue. The HSD17B12KO mice die at E9.5 at latest and present severe developmental defects. Analysis of the knockout embryos revealed that the embryos initiate gastrulation, but organogenesis is severely disrupted. As a result, the E8.5-E9.5 embryos were void of all normal morphological structures. In addition, the inner cell mass of knockout blastocysts showed decreased proliferation capacity in vitro, and the amount of arachidonic acid was significantly decreased in heterozygous HSD17B12 ES cells. This, together with the expression pattern, suggests that in mouse, the HSD17B12 is involved in the synthesis of arachidonic acid and is essential for normal neuronal development during embryogenesis.

The Expression of HSD17B12 Is Associated with COX-2 Expression and Is Increased in High-Grade Epithelial Ovarian Cancer

“…It has also been shown that silencing HSD17B12 expression with siRNA in an ovarian cancer cell line led to growth inhibition and increased apoptosis [14]. These data are in line with our data on HSD17B12 knockout mice, indicating an essential role for the enzyme in cell proliferation and differentiation during mouse development [15]. In all these studies, the growthpromoting effect of HSD17B12 was related to its role in AA production and not to the synthesis of estradiol.…”

The Amazing Power of Cancer Cells to Recapitulate Extraembryonic Functions: The Cuckoo's Tricks

“…The yolk sac uses high-density lipoproteins (HDLs) and very-low-density lipoproteins (VLDL) as carriers to incorporate cholesterol from the maternal circulation and to transfer it to the embryonic side [16]. In turn, the interstitial lipid accumulation of cholesterol, a precursor molecule of many hormones like aldosterone, corticoids, androgens, strogens, and progesterone, may favor fluid infiltration and cell migration, proliferation, and differentiation during embryo development [19]. The ability to transport fat in the form of lipoprotein through the circulatory system by eukaryotes is one of their most significant functions right from the beginning of existence [20].…”

Remodeling adipose tissue through in silico modulation of fat storage for the prevention of type 2 diabetes

“…It is unknown if the inhibition of the respective enzymes in adults would also be lethal. Four other potential targets (Enolase 1 ( ENO1 ), Dihydrolipoamide Dehydrogenase ( DLD ), Glyceraldehyde-3-Phosphate Dehydrogenase ( GAPDH ) and Hydroxysteroid 17-Beta Dehydrogenase 12 ( HSD17B1 2)) are also essential in most of those cell lines and homozygous null mouse models for each of these genes die at the embryonic state [59–62]. It has been shown that HSD17B12 knock down is linked to reduced lipid accumulation in adipocytes which would match the effect predicted by the network [63].…”