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Matti Poutanen - One of the best experts on this subject based on the ideXlab platform.
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Role of hydroxysteroid (17beta) dehydrogenase type 1 in reproductive tissues and hormone-dependent diseases
Molecular and Cellular Endocrinology, 2019Co-Authors: Taija Heinosalo, Niina Saarinen, Matti PoutanenAbstract:Abstract Abnormal synthesis and metabolism of sex steroids is involved in the pathogenesis of various human diseases, such as endometriosis and cancers arising from the breast and uterus. Steroid biosynthesis is a multistep enzymatic process proceeding from cholesterol to highly active sex steroids via different intermediates. Human Hydroxysteroid (17beta) dehydrogenase 1 (HSD17B1) enzyme shows a high capacity to produce the highly active estrogen, estradiol, from a precursor hormone, estrone. However, the enzyme may also play a role in other steps of the steroid biosynthesis pathway. In this article, we have reviewed the literature on HSD17B1, and summarize the role of the enzyme in hormone-dependent diseases in women as evidenced by preclinical studies.
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HSD17B1 expression induces inflammation-aided rupture of mammary gland myoepithelium.
Endocrine-related cancer, 2018Co-Authors: Päivi Järvensivu, Taija Heinosalo, Niina Saarinen, Janne Hakkarainen, Pauliina Kronqvist, Matti PoutanenAbstract: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 in vivo and indicate that HSD17B1 is a factor inducing phenotypic alterations associated with mammary tumorigenesis.
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Deleting the mouse HSD17B1 gene results in a hypomorphic Naglu allele and a phenotype mimicking a lysosomal storage disease.
Scientific reports, 2017Co-Authors: Heli Jokela, Janne Hakkarainen, Laura Kätkänaho, Pirjo Pakarinen, Suvi T. Ruohonen, Manuel Tena-sempere, Fu-ping Zhang, Matti PoutanenAbstract: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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Hydroxysteroid (17β)‐dehydrogenase 1‐deficient female mice present with normal puberty onset but are severely subfertile due to a defect in luteinization and progesterone production
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2015Co-Authors: Janne Hakkarainen, Heli Jokela, Laura Kätkänaho, Pirjo Pakarinen, Fu-ping Zhang, Claes Ohlsson, Hanna Heikelä, Liesbeth Vandenput, Matti PoutanenAbstract:Hydroxysteroid (17β)-dehydrogenase type 1 (HSD17B1) catalyzes the conversion of low active 17-ketosteroids, androstenedione (A-dione) and estrone (E1) to highly active 17-hydroxysteroids, testoster...
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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
Chemico-biological interactions, 2015Co-Authors: Päivi Järvensivu, Niina Saarinen, Pasi Koskimies, Taija Saloniemi-heinonen, Michael Awosanya, Matti PoutanenAbstract: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.
Keizo Ohnaka - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in cyp19a1 HSD17B1 and hsd17b2 genes and serum sex hormone level among postmenopausal japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Abstract Objective Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. Methods We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography–tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. Results After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Conclusions Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI.
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Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone level among postmenopausal Japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography-tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Satoyo Hosono - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in cyp19a1 HSD17B1 and hsd17b2 genes and serum sex hormone level among postmenopausal japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Abstract Objective Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. Methods We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography–tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. Results After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Conclusions Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI.
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Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone level among postmenopausal Japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography-tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Sadao Suzuki - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in cyp19a1 HSD17B1 and hsd17b2 genes and serum sex hormone level among postmenopausal japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Abstract Objective Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. Methods We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography–tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. Results After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Conclusions Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI.
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Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone level among postmenopausal Japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography-tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Haruo Mikami - One of the best experts on this subject based on the ideXlab platform.
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polymorphisms in cyp19a1 HSD17B1 and hsd17b2 genes and serum sex hormone level among postmenopausal japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Abstract Objective Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. Methods We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography–tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. Results After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Conclusions Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI.
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Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone level among postmenopausal Japanese women
Maturitas, 2015Co-Authors: Satoyo Hosono, Hidemi Ito, Isao Oze, Yasuki Higaki, Emi Morita, Naoyuki Takashima, Sadao Suzuki, Keiichi Shimatani, Haruo Mikami, Keizo OhnakaAbstract:Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight. We conducted a cross-sectional study. 785 Japanese natural postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography-tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with differences in serum estradiol level. None of these polymorphisms showed a significant interaction with current body mass index (BMI). Our findings suggested that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.