HSD17B1 expression enhances estrogen signaling stimulated by the low active estrone, evidenced by an estrogen responsive element-driven reporter gene in vivo

Järvensivu, Päivi; Saloniemi-Heinonen, Taija; Awosanya, Michael; Koskimies, Pasi; Saarinen, Niina M.; Poutanen, Matti

doi:10.1016/j.cbi.2015.01.008

Cited by 12 publications

(13 citation statements)

References 83 publications

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“…The mice were housed under a 12-h light/darkness cycle at 21 ± 1°C, and they had free access to soy-free RM3 chow (Special Diet Service, Whitman Essex, UK) and tap water. The generation and maintenance of FVB/N mice expressing human HSD17B1 under the chicken betaactin promoter (HSD17B1TG mice) have been previously described (Saloniemi et al 2010, Järvensivu et al 2015. Briefly, HSD17B1TG males from line 013 and WT females were bred together, and heterozygous HSD17B1TG female offspring were used in the studies.…”

Section: Experimental Animals and Timeline Of Studiesmentioning

confidence: 99%

“…In addition, bi-transgenic ERELuc-HSD17B1TG mice carrying an estrogen-response element (ERE)-driven luciferase reporter gene (Lemmen et al 2004) in the HSD17B1 genetic background were used for mammary gland estrogen activity assays ex vivo. The maintenance and genotyping of these mice have been previously described (Järvensivu et al 2015). A summary timeline diagram of the mouse experiments and analyses performed is presented in Supplementary Fig.…”

Section: Experimental Animals and Timeline Of Studiesmentioning

confidence: 99%

“…In this study, we investigated the impact of HSD17B1 expression on mammary gland tissue by using transgenic mice with universal overexpression of human HSD17B1 (HSD17B1TG mice) (Saloniemi et al 2007). We previously reported that HSD17B1TG mice have increased in vivo production of E2 from E1 (Saloniemi et al 2010, Järvensivu et al 2015 and that HSD17B1TG female mice develop a classical estrogen-induced endometrial hyperplasia phenotype, indicating enhanced estrogen action in estrogen target tissues. In the present study, we report HSD17B1-induced effects on the mammary gland both in HSD17B1TG female mice and in wild-type (WT) mice with local human HSD17B1 overexpression in the mammary gland induced by transplanting human HSD17B1-expressing mammary epithelium into WT mammary gland.…”

Section: Introductionmentioning

confidence: 99%

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HSD17B1 expression induces inflammation-aided rupture of mammary gland myoepithelium

Järvensivu

Heinosalo

Hakkarainen

et al. 2018

Endocrine-Related Cancer

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Hydroxysteroid (17-beta) dehydrogenase type 1 (HSD17B1) converts low-active estrogen estrone to highly active estradiol. Estradiol is necessary for normal postpubertal mammary gland development; however, elevated estradiol levels increase mammary tumorigenesis. To investigate the significance of the human HSD17B1 enzyme in the mammary gland, transgenic mice universally overexpressing human HSD17B1 were used (HSD17B1TG mice). Mammary glands obtained from HSD17B1TG females at different ages were investigated for morphology and histology, and HSD17B1 activity and estrogen receptor activation in mammary gland tissue were assessed. To study the significance of HSD17B1 enzyme expression locally in mammary gland tissue, HSD17B1-expressing mammary epithelium was transplanted into cleared mammary fat pads of wild-type females, and the effects on mammary gland estradiol production, epithelial cells and the myoepithelium were investigated. HSD17B1TG females showed increased estrone to estradiol conversion and estrogen-response element-driven estrogen receptor signaling in mammary gland tissue, and they showed extensive lobuloalveolar development that was further enhanced by age along with an increase in serum prolactin concentrations. At old age, HSD17B1TG females developed mammary cancers. Mammary-restricted HSD17B1 expression induced lesions at the sites of ducts and alveoli, accompanied by peri- and intraductal inflammation and disruption of the myoepithelial cell layer. The lesions were shown to be estrogen dependent, as treatment with an antiestrogen, ICI 182,780, starting when lesions were already established reversed the phenotype. These data elucidate the ability of human HSD17B1 to enhance estrogen action in the mammary gland and indicate that HSD17B1 is a factor inducing phenotypic alterations associated with mammary tumorigenesis.

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Section: Experimental Animals and Timeline Of Studiesmentioning

confidence: 99%

Section: Experimental Animals and Timeline Of Studiesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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HSD17B1 expression induces inflammation-aided rupture of mammary gland myoepithelium

Järvensivu

Heinosalo

Hakkarainen

et al. 2018

Endocrine-Related Cancer

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“…HSD17B2 and HSD17B1 react with one another, and HSD17B2 catalyzes the formation of E1 and 4‐AD, with E2 and T acting as substrates under the action of a coenzyme (NAD or NADP). [ 29 ] Although HSD17B2 and HSD17B1 catalyze the same enzymatic reaction, their sequences only share a limited sequence identity. [ 30 ] According to the results on LA metabolism in mouse plasma, we speculated that the four hormones might be altered because LA acted as an agonist of HSD17B1 or an inhibitor of HSD17B2.…”

Section: Discussionmentioning

confidence: 99%

Lepidiline A Improves the Balance of Endogenous Sex Hormones and Increases Fecundity by Targeting HSD17B1

Cheng

Shen

Ding

et al. 2020

Molecular Nutrition Food Res

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Scope: Maca (Lepidium meyenii), a well-known plant from the Andean highlands of Peru, has been used widely as a nutritional supplement to increase sexual function and fecundity. However, the identity of its active ingredients and how they function remain unknown. Methods and results: Chemical substances in maca are identified by UPLC-Q-TOF, and the active ingredients are screened through HotMap coupled with an artificial neural network. Lepidiline A (LA), an imidazole alkaloid, is identified as the key active compound. LA affects the balance of endogenous sex hormones in mice and improves fecundity in Drosophila. Using a molecular LA probe, 17ß-hydroxysteroid dehydrogenase type 1 (HSD17B1) is revealed to be the potential target of LA using a fishing-rod strategy. It is demonstrated with experimental data that LA targets HSD17B1 to enhance the enzyme's activity and increases its bioconversion efficiency of actively formed sex hormones including estrogen to 17 -estradiol and 4-androsten-3,7-dione to testosterone, which ultimately improves reproductive activity. Conclusion: LA improves the balance of endogenous sex hormones and increases fecundity by targeting HSD17B1. This underlying mechanism of action provides a useful insight into the application of maca in the regulation of dietary nutrition and healthy fertility.

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“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2020

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Beta-hydroxysteroid dehydrogenases (β-HSDs) are a group of steroidogenic enzymes that are involved in steroid biosynthesis and metabolism, and play a crucial role in mammalian physiology and development, including sex determination and differentiation. In the present study, a genome-wide analysis identified the numbers of β-hsd genes in orange-spotted grouper (Epinephelus coioides) (19), human (Homo sapiens) (22), mouse (Mus musculus) (24), chicken (Gallus gallus) (16), xenopus (Xenopus tropicalis) (24), coelacanth (Latimeria chalumnae) (17), spotted gar (Lepisosteus oculatus) (14), zebrafish (Danio rerio) (19), fugu (Takifugu rubripes) (19), tilapia (Oreochromis niloticus) (19), medaka (Oryzias latipes) (19), stickleback (Gasterosteus aculeatus) (17) and common carp (Cyprinus carpio) (27) samples.A comparative analysis revealed that the number of β-hsd genes in teleost fish was no greater than in tetrapods due to gene loss followed by a teleost-specific whole-genome duplication event. Based on transcriptome data from grouper brain and gonad samples during sex reversal, six β-hsd genes had relatively high expression levels in the brain, indicating that these genes may be required for neurogenesis or the maintenance of specific biological processes in the brain. In the gonad, two and eight β-hsd genes were up-and downregulated, respectively, indicating their important roles in sex reversal. Our results demonstrated that β-hsd genes may be involved in the sex reversal of grouper by regulating the synthesis and metabolism of sex steroid hormones.

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HSD17B1 expression enhances estrogen signaling stimulated by the low active estrone, evidenced by an estrogen responsive element-driven reporter gene in vivo

Cited by 12 publications

References 83 publications

HSD17B1 expression induces inflammation-aided rupture of mammary gland myoepithelium

HSD17B1 expression induces inflammation-aided rupture of mammary gland myoepithelium

Lepidiline A Improves the Balance of Endogenous Sex Hormones and Increases Fecundity by Targeting HSD17B1

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

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