title: HSD17B1 expression enhances estrogen signaling stimulated by the low active estrone, evidenced by an estrogen responsive element-driven reporter gene in vivo.
abstract: Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) belongs to a family of short-chain-dehydrogenases. The enzyme utilizes NAD(P) and NAD(P)H as cofactors, and catalyzes the reversible reaction between estrone (E1) and estradiol (E2) in vitro. Of these steroids, E1 presents with lower estrogenic activity, but is converted to highly active E2 by HSD17B1. HSD17B1 is expressed especially in tissues with a high E2-producing capacity such as human ovaries and placenta, but also in several peripheral estrogen target tissues in humans, and inhibiting the enzyme activity is, thus, considered a promising approach to treat estrogen-dependent diseases. By analyzing transgenic mice universally expressing human HSD17B1 and carrying estrogen-response element (ERE)-driven luciferase reporter gene (Bi-transgenic ERELuc-HSD17B1TG mice) we showed a markedly higher reporter gene activity in various peripheral tissues of these mice as compared with ERELuc mice, indicating enhanced estrogen response generated by human HSD17B1 expression. An increased response after E1 administration was also evident in the Bi-TG mice, indicated by the increased uterus growth response and by the higher ERELuc reporter gene activity in the uterus. Moreover, a HSD17B1 inhibitor significantly reduced E1-induced increase in the uterus weight and uterine epithelial proliferation in the Bi-TG mice. Also the E1-induced ERELuc activity in the inhibitor-treated uterus was reduced by the HSD17B1 inhibitor in immature mice ex vivo, as well as in the liver of adult mice. The data, thus, demonstrate the potential use of the Bi-TG mice as a preclinical in vivo model for screening the efficacy of HSD17B1 inhibitors. As compared with the existing models, the Bi-TG mice present with luciferase activity as an additional, easily quantitative endpoint for the estrogen action.
authors.affiliation: Department of Physiology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Järvensivu
authors.affiliation: Department of Physiology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
authors.forename: Taija
authors.initials: T
authors.lastname: Saloniemi-Heinonen
authors.affiliation: Department of Physiology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland.
authors.forename: Michael
authors.initials: M
authors.lastname: Awosanya
authors.affiliation: Forendo Pharma Ltd., Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Koskimies
authors.affiliation: Functional Foods Forum, Itäinen Pitkäkatu 4, FIN-20520 Turku, Finland.
authors.forename: Niina
authors.initials: N
authors.lastname: Saarinen
authors.affiliation: Department of Physiology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland; Turku Center for Disease Modeling, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. Electronic address: matti.poutanen@utu.fi.
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D004960:Estradiol Dehydrogenases / Q000235:genetics*; D004967:Estrogens / Q000235:genetics*; D004970:Estrone / Q000235:genetics*; D005260:Female; D017930:Genes, Reporter / Q000235:genetics*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D014599:Uterus / Q000187:drug effects / Q000201:enzymology
chemical_list: D004791:Enzyme Inhibitors; D004967:Estrogens; D004970:Estrone; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human
keywords: Estrogen reporter; HSD17B1 inhibitors; Hydroxysteroid (17beta) dehydrogenase 1; Luciferase; Transgenic mice; Uterus