The Hydroxysteroid (17β) Dehydrogenase Family Gene HSD17B12 Is Involved in the Prostaglandin Synthesis Pathway, the Ovarian Function, and Regulation of Fertility

Abstract

The hydroxysteroid (17beta) dehydrogenase (HSD17B)12 gene belongs to the hydroxysteroid (17β) dehydrogenase superfamily, and it has been implicated in the conversion of estrone to estradiol as well as in the synthesis of arachidonic acid (AA). AA is a precursor of prostaglandins, which are involved in the regulation of female reproduction, prompting us to study the role of HSD17B12 enzyme in the ovarian function. We found a broad expression of HSD17B12 enzyme in both human and mouse ovaries. The enzyme was localized in the theca interna, corpus luteum, granulosa cells, oocytes, and surface epithelium. Interestingly, haploinsufficiency of the HSD17B12 gene in female mice resulted in subfertility, indicating an important role for HSD17B12 enzyme in the ovarian function. In line with significantly increased length of the diestrous phase, the HSD17B females gave birth less frequently than wild-type females, and the litter size of HSD17B12 females was significantly reduced. Interestingly, we observed meiotic spindle formation in immature follicles, suggesting defective meiotic arrest in HSD17B12 ovaries. The finding was further supported by transcriptome analysis showing differential expression of several genes related to the meiosis. In addition, polyovular follicles and oocytes trapped inside the corpus luteum were observed, indicating a failure in the oogenesis and ovulation, respectively. Intraovarian concentrations of steroid hormones were normal in HSD17B12 females, whereas the levels of AA and its metabolites (6-keto prostaglandin F1alpha, prostaglandin D, prostaglandin E, prostaglandin F, and thromboxane B) were decreased. In conclusion, our study demonstrates that HSD17B12 enzyme plays an important role in female fertility through its role in AA metabolism.

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

“…The sections were incubated overnight with one of the primary antibodies at 4 ° C (HSD17B12 [13], ELOVL5 [19], and COX-2 [20][21][22][23]), diluted in 3% bovine serum albumin + 10% normal goat serum in PBST ( Table 2). On the following day, endogenous peroxidase activity was blocked with 3% H 2 O 2 (Sigma-Aldrich, St. Louis, MO, USA) treatment (20 min, room temperature).…”

Genome-Wide Analysis and Function Prediction of Long Noncoding RNAs in Sheep Pituitary Gland Associated with Sexual Maturation

“…In our study, HSD17B12 was enriched for steroid hormone biosynthesis and the expression level of HSD17B12, FSH and LH were decreased after disturbing the expression of lncRNA TCONS_00066406. A previous study has shown that HSD17B12 can effect female reproduction through regulating prostaglandin synthesis [66], which further proved the importance of HSD17B12 in reproduction and prompted the potential role of antisense-interact lncRNA TCONS_00066406 on reproduction. DCBLD2 was recognized as the crucial regulation factor in tumorigenesis [67] and we found it was enriched in growth related pathways, suggesting lncRNA XR_003591760.1 possibly regulates pituitary development by interacting with DCBLD2.…”

Beta-Hydroxysteroid Dehydrogenase Genes in Orange-Spotted Grouper (Epinephelus coioides): Genome-Wide Identification and Expression Analysis During Sex Reversal

“…HSD17B1 is mainly expressed in the ovary , and catalyzes lower estrogenic active estrone (E1) to highly active estradiol (E2) (Hakkarainen et al, 2015;Jarvensivu et al, 2015). HSD17B12 has been implicated in the conversion of estrone to estradiol as well as in the synthesis of arachidonic acid (AA), and plays important roles in ovarian function and female fertility (Kemilainen et al, 2016). Accordingly, we propose that the high expression levels of hsd17b1, hsd17b12a and hsd17b 12b in the ovary may be due to its involvement in the maintenance of the ovary, and the degeneration of ovary leads to the downregulation of these genes during the sex reversal grouper.…”