Overexpression of human estrogen biosynthetic enzyme Hydroxysteroid (17beta) dehydrogenase type 1 which induces adenomyosis-like phenotype in transgenic mice
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ABSTRACT:
PROVIDER: PRJNA820290 | ENA |
REPOSITORIES: ENA
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Project description:We report uterine mRNA transcriptome sequencing of mice over-expressing human estrogen biosynthetic enzyme HSD17B1 (HSD17B1TG mice) present with adenomyosis phenotype.
2022-05-17 | GSE199492 | GEO
Project description:The maturation-inducing hormone 17alpha,20beta-dihydroxy-4-pregnen-3-one (DHP) was first identified in the amago salmon. However, although carbonyl reductase-like 20beta-hydroxysteroid dehydrogenase (CR/20beta-HSD) was reported to convert 17alpha-hydroxyprogesterone (17alpha-P) to DHP in rainbow trout, we previously found that CR/20beta-HSD mRNA was not up-regulated in stimulated granulosa cells from masu salmon, which suggests that DHP is synthesized by a different enzyme. Accordingly, the present study aimed to identify the specific 20beta-hydroxysteroid dehydrogenase (20beta-HSD) responsible for DHP production by granulosa cells during final oocyte maturation in masu salmon. Granulosa layers were isolated from ovarian follicles at one month before ovulation and incubated with or without forskolin, which was used to mimic luteinizing hormone. Subsequent RNA-sequencing yielded ~12 million reads, with an average length of 51 bp, and 71,062 contigs of >100 bp were constructed. Of the 953 contigs that were exclusively constructed from the reads of forskolin-induced granulosa layers, tBlastx analysis identified one contig (#f103496) that matched 17beta-hydroxysteroid dehydrogenase type 12. We found that mammalian cells transfected with full-length omhsd17beta12l exhibited considerable 20beta-HSD activity, as indicated by efficient conversion of exogenous 17alpha-P to DHP. In addition, we found that omhsd17beta12l mRNA levels were consistently low in follicles during vitellogenic growth; however, the levels increased significantly during final oocyte maturation. The levels of omhsd17beta12l mRNA were also considerably increased in granulosa layers in which 20beta-HSD activity was induced by salmon pituitary extract. Therefore, we suggest that omhsd17beta12l, not CR/20beta-HSD, is the 20beta-HSD responsible for DHP production by granulosa cells in masu salmon during final oocyte maturation. Comparison of mRNA levels between control and forskolin-incubated sample.
2016-08-04 | E-GEOD-85134 | biostudies-arrayexpress
Project description:Experimental design: Endometrial tumours were induced orthotopically (in one uterine horn) in 8-week-old female athymic nude mice (Crl:NU(NCr)-Foxn1nu), using an Ishikawa-derived cell line (clones Ishi-M3-HSDA, described in Konings et al 2018). This cell line maintains the characteristics of the parental line (i.e., gives rise to well differentiated-estrogen sensitive adenocarcinomas) and further bears the luciferase gene for in vivo measurement of tumour growth by bioluminescence and expresses the enzyme 17β-hydroxysteroid dehydrogenase (HSD17B1). After tumour engraftment (approximately two weeks), baseline was defined, mice were ovariectomised (to remove the natural source of estrogens) and estrone was supplemented via subcutaneous pellets at a dose of 0.02 g/day. Mice were further assigned to one arm, receiving only estrone, and a second arm, receiving estrone plus the HSD17B1 inhibitor FP4643 at a dose of 25mg/Kg. At humane endpoint (approximately 10 weeks), mice were sacrificed, primary tumours were excised and snap-frozen. Tumours were divided on their largest diameter plane and slices for RNA isolation were prepared from such largest surface area of the primary tumours. Histology on mirror slices confirmed the present of tumour tissue and the absence of necrosis, inflammation and mouse endometrium.
2021-04-09 | E-MTAB-10338 | biostudies-arrayexpress
Project description:The hippocampus is especially susceptible to age-associated neuronal pathologies, and there is concern that the age-associated rise in cortisol secretion from the adrenal gland may contribute to their etiology. Furthermore, because 11β-hydroxysteroid dehydrogenase type 1 (HSD11B1) catalyzes the reduction of cortisone to the active hormone cortisol, it is plausible that an increase in the expression of this enzyme enhances the deleterious impact of cortisol in the hippocampus and contributes to the neuronal pathologies that underlie cognitive decline in the elderly. Rhesus macaques were used as a translational animal model of human aging, to examine age-related changes in gene and protein expressions of (HSD11B1/HSD11B1) in the hippocampus, a region of the brain that plays a crucial role in learning and memory. Older animals showed significantly (p<0.01) higher base-line cortisol levels in the circulation. In addition, they showed significantly (p<0.05) higher hippocampal expression of HSD11B1 but not NR3C1 and NR3C2 (i.e., two receptor-encoding genes through which cortisol exerts its physiological actions). A similar age-related significant (p<0.05) increase in the expression of the HSD11B1 was revealed at the protein level by Western blot analysis. The data suggest that an age-related increase in the expression of hippocampal HSD11B1 is likely to raise cortisol concentrations in this cognitive brain area, and thereby contribute to the etiology of neuropathologies that ultimately lead to neuronal loss and dementia. Targeting this enzyme pharmacologically may help to reduce the negative impact of elevated cortisol concentrations within glucocorticoid-sensitive brain areas and thereby afford neuronal protection.
2024-04-03 | GSE249907 | GEO
Project description:17beta-hydroxysteroid dehydrogenase type12 (HSD17B12) has been demonstrated to be involved in regulation of in situ biosynthesis of estradiol (E2). HSD17B12 expression was reported in breast carcinomas but its functions have remained unknown. Therefore, we examined the correlation between mRNA expression profiles determined by microarray analysis and tissue E2 concentrations obtained from 16 postmenopausal breast carcinoma cases in order to analyze an association of the enzyme expression with intratumoral E2 production. No significant correlations were detected between intratumoral HSD17B12expression and E2 concentration.These findings suggest that the presence of HSD17B12 in carcinoma cells contributes to a development of human breast carcinoma via a pathway other than in situ E2 biosynthesis.
2008-12-31 | GSE11965 | GEO
Project description:Human blood platelets have important, regulatory functions in diverse hemostatic and pathological disorders, including vascular remodeling, inflammation, and wound repair. Microarray analysis was used to study the molecular basis of essential thrombocythemia, a myeloproliferative disorder with quantitative and qualitative platelet defects associated with cardiovascular and thrombohemorrhagic symptoms, not infrequently neurological. A platelet-expressed gene (HSD17B3) encoding type 3 17beta-hydroxysteroid dehydrogenase (previously characterized as a testis-specific enzyme catalyzing the final step in gonadal synthesis of testosterone) was selectively down-regulated in ET platelets, with reciprocal induction of the type 12 enzyme (HSD17B12). Functional 17beta-HSD3 activity corresponding to approximately 10% of that found in murine testis was demonstrated in normal platelets. The induction of HSD17B12 in ET platelets was unassociated with a concomitant increase in androgen biosynthesis, suggesting distinct functions and/or substrate specificities of the types 3 and 12 enzymes. Application of a molecular assay distinguished ET from normal platelets in 20 consecutive patients (p < 0.0001). These data provide the first evidence that distinct subtypes of steroidogenic 17beta-HSDs are functionally present in human blood platelets, and that the expression patterns of HSD17B3 and HSD17B12 are associated with an uncommon platelet disorder manifest by quantitative and qualitative platelet defects.
2007-08-31 | E-GEOD-2006 | biostudies-arrayexpress
Project description:Nuclear NAD+-biosynthetic enzyme NMNAT1 facilitates survival of developing retinal neurons
| PRJNA738469 | ENA
Project description:Human blood platelets have important, regulatory functions in diverse hemostatic and pathological disorders, including vascular remodeling, inflammation, and wound repair. Microarray analysis was used to study the molecular basis of essential thrombocythemia, a myeloproliferative disorder with quantitative and qualitative platelet defects associated with cardiovascular and thrombohemorrhagic symptoms, not infrequently neurological. A platelet-expressed gene (HSD17B3) encoding type 3 17beta-hydroxysteroid dehydrogenase (previously characterized as a testis-specific enzyme catalyzing the final step in gonadal synthesis of testosterone) was selectively down-regulated in ET platelets, with reciprocal induction of the type 12 enzyme (HSD17B12). Functional 17beta-HSD3 activity corresponding to approximately 10% of that found in murine testis was demonstrated in normal platelets. The induction of HSD17B12 in ET platelets was unassociated with a concomitant increase in androgen biosynthesis, suggesting distinct functions and/or substrate specificities of the types 3 and 12 enzymes. Application of a molecular assay distinguished ET from normal platelets in 20 consecutive patients (p < 0.0001). These data provide the first evidence that distinct subtypes of steroidogenic 17beta-HSDs are functionally present in human blood platelets, and that the expression patterns of HSD17B3 and HSD17B12 are associated with an uncommon platelet disorder manifest by quantitative and qualitative platelet defects. Keywords: other
2005-11-23 | GSE2006 | GEO
Project description:Pharmacological inhibition of 17β-hydroxysteroid dehydrogenase inhibits endometrial cancer growth in an orthotopic xenograft mouse model
| PRJEB44184 | ENA
Project description:17β-hydroxysteroid dehydrogenase-13 (17β-HSD13) is a liver-rich lipid droplet associated protein, encoding by gene HSD17B13, that acted as an important regulator of hepatic lipid metabolism. Increased expression of 17β-HSD13 promotes hepatic lipid accumulation in rodents, and a common loss-of-function variant of HSD17B13 (rs72613567: TA) is related to better outcome in patients with various chronic liver diseases. To understand the role of 17β-HSD13 in liver lipid metabolism under normal and high-fat feeding conditions, we characterized the effect of protein phosphorylation of 17β-HSD13 on hepatic lipid homeostasis. We identify Ser33 as an important protein kinase A (PKA)-mediated phosphorylation site of 17β-HSD13 that physically interact with ATGL and facilitates its translocation to lipid droplets to enhance lipolysis. Mutation of Ser33 to Ala (S33A) in 17β-HSD13 reduces ATGL-dependent lipolysis and increases lipid droplet size in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Consistently, a transgenic knock-in mouse strain carrying HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops liver steatosis with reduced lipolysis. Moreover, HSD17B1333A/A mice are more prone to high fat-induced hepatic steatosis and inflammation. Finally, we found Reproterol, a potential HSD17B13 modulator and FDA-approved drug, confers a protection against liver steatosis possibly through phosphorylation of 17β-HSD13 at Ser33 in a PKA-dependent manner. In summary, we demonstrate a critical role and the underlying mechanism of hepatic 17β-HSD13 phosphorylation in the pathogenesis of NAFLD. Our findings highlight the potential of targeting 17β-HSD13 phosphorylation as a novel therapeutic approach for NAFLD.
2023-03-11 | PXD037262 | Pride