Hydroxysteroid (17b)-dehydrogenase type 1 (HSD17B1) catalyzes the conversion of low active 17-ketosteroids, androstenedione (A-dione) and estrone (E1) to highly active 17-hydroxysteroids, testosterone (T) and E2, respectively. In this study, the importance of HSD17B1 in ovarian estrogen production was determined using Hsd17b1 knockout (HSD17B1KO) mice. In these mice, the ovarian HSD17B enzyme activity was markedly reduced, indicating a central role of HSD17B1 in ovarian physiology. The lack of Hsd17b activity resulted in increased ovarian E1:E2 and A-dione:T ratios, but we also observed reduced progesterone concentration in HSD17B1KO ovaries. Accordingly with the altered steroid production, altered expression of Star, Cyp11a1, Lhcgr, Hsd17b7, and especially Cyp17a1 was observed. The ovaries of HSD17B1KO mice presented with all stages of folliculogenesis, while the corpus luteum structure was less defined and number reduced. Surprisingly, bundles of large granular cells of unknown origin appeared in the stroma of the KO ovaries. The HSD17B1KO mice presented with severe subfertility and failed to initiate pseudopregnancy. However, the HSD17B1KO females presented with normal estrous cycle defined by vaginal smears and normal puberty appearance. This study indicates that HSD17B1 is a key enzyme in ovarian steroidogenesis and has a novel function in initiation and stabilization of pregnancy.-Hakkarainen, J., Jokela, H., Pakarinen, P., Heikelä, H., Kätkänaho, L., Vandenput, L., Ohlsson, C., Zhang, F.-P., Poutanen, M. Hydroxysteroid (17b)-dehydrogenase 1-deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production. FASEB J. 29, 3806-3816 (2015). www.fasebj.org Key Words: ovary • estrogen • fertility • HSD17B enzymes HYDROXYSTEROID (17b)-DEHYDROGENASES (HSD17BS) ARE ENZYMES CATALYZING the conversion of low active 17-ketosteroids to the highly active 17b hydroxysteroids, and vice versa. Many of the enzymes catalyze both oxidative (17-hydroxy to 17-keto) and reductive (17-keto to 17-hydroxy) activity with a proper cofactor added in vitro. The conversion of 17-ketosteroid to the 17b-hydroxysteroid is an essential step in the formation of the classic highly active sex steroids E2 and testosterone (T). Most of the HSD17B enzymes belong to the family of short-chain dehydrogenases/ reductases, while some are members of the aldo-keto reductase family (1).All enzymes with HSD17B activity present with distinct cell-specific expression, different substrate specificities, and unique regulatory mechanisms (2, 3). Current evidence indicates differential physiologic roles of the various HSD17B enzymes, and it is expected that some of the HSD17B enzymes act also in metabolic pathways other than those involved in sex steroid metabolism. Among those, HSD17B4 has been shown to be involved in b--oxidation of fatty acids (1, 4), HSD17B7 in cholesterol biosynthesis (5), and HSD17B10 and -12 in fatty acid metabolism (6).The human HSD17B1 enzyme prefera...
HSD17B1 is a steroid metabolising enzyme. We have previously generated knockout mice that had the entire coding region of Hsd17b1 replaced with lacZ-neo cassette (Hsd17b1-LacZ/Neo mice). This resulted in a 90% reduction of HSD17B1 activity, associated with severe subfertility in the knockout females. The present study indicates that Hsd17b1-LacZ/Neo male mice have a metabolic phenotype, including reduced adipose mass, increased lean mass and lipid accumulation in the liver. During the characterisation of this metabolic phenotype, it became evident that the expression of the Naglu gene, located closely upstream of Hsd17b1, was severely reduced in all tissues analysed. Similar results were obtained from Hsd17b1-LacZ mice after removing the neo cassette from the locus or by crossing the Hsd17b1-LacZ/Neo mice with transgenic mice constitutively expressing human HSD17B1. The deficiency of Naglu caused the accumulation of glycosaminoglycans in all studied mouse models lacking the Hsd17b1 gene. The metabolic phenotypes of the Hsd17b1 knockout mouse models were recapitulated in Naglu knockout mice. Based on the data we propose that the Hsd17b1 gene includes a regulatory element controlling Naglu expression and the metabolic phenotype in mice lacking the Hsd17b1 genomic region is caused by the reduced expression of Naglu rather than the lack of Hsd17b1.
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