The Experts below are selected from a list of 159656712 Experts worldwide ranked by ideXlab platform
Damjana Rozman - One of the best experts on this subject based on the ideXlab platform.
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cytochrome p450 metabolism of the post lanosterol intermediates explains enigmas of cholesterol synthesis
Scientific Reports, 2016Co-Authors: Jure Acimovic, Rok Košir, Martina Perše, Sandeep Goyal, Marko Golicnik, Ales Belic, žiga Urlep, Peter F Guengerich, Damjana RozmanAbstract:Cholesterol synthesis is among the oldest metabolic pathways, consisting of the Bloch and Kandutch-Russell branches. Following lanosterol, sterols of both branches are proposed to be dedicated to cholesterol. We challenge this dogma by mathematical modeling and with experimental evidence. It was not possible to explain the sterol profile of testis in cAMP responsive element modulator tau (Crem τ) knockout mice with mathematical models based on textbook pathways of cholesterol synthesis. Our model differs in the inclusion of virtual sterol metabolizing enzymes branching from the pathway. We tested the hypothesis that enzymes from the cytochrome P450 (CYP) superfamily can participate in the catalysis of non-classical reactions. We show that CYP enzymes can metabolize multiple sterols in vitro, establishing novel branching points of cholesterol synthesis. In conclusion, sterols of cholesterol synthesis can be oxidized further to metabolites not dedicated to production of cholesterol. Additionally, CYP7A1, CYP11A1, CYP27A1, and CYP46A1 are parts of a broader cholesterol synthesis network.
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circadian expression of steroidogenic cytochromes p450 in the mouse adrenal gland involvement of camp responsive element modulator in epigenetic regulation of CYP17A1
FEBS Journal, 2012Co-Authors: Rok Košir, Ursula Prosenc Zmrzljak, Tanja Bele, Jure Acimovic, Martina Perše, Gregor Majdic, Cornelia Prehn, Jerzy Adamski, Damjana RozmanAbstract:The cytochrome P450 (CYP) genes Cyp51, Cyp11a1, CYP17A1, Cyb11b1, Cyp11b2 and Cyp21a1 are involved in the adrenal production of corticosteroids, whose circulating levels are circadian. cAMP signaling plays an important role in adrenal steroidogenesis. By using cAMP responsive element modulator (Crem) knockout mice, we show that CREM isoforms contribute to circadian expression of steroidogenic CYPs in the mouse adrenal gland. Most striking was the CREM-dependent hypomethylation of the CYP17A1 promoter at zeitgeber time 12, which resulted in higher CYP17A1 mRNA and protein expression in the knockout adrenal glands. The data indicate that products of the Crem gene control the epigenetic repression of Cyp17 in mouse adrenal glands.
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Circadian expression of steroidogenic cytochromes P450 in the mouse adrenal gland – involvement of cAMP‐responsive element modulator in epigenetic regulation of CYP17A1
The FEBS journal, 2011Co-Authors: Rok Košir, Ursula Prosenc Zmrzljak, Tanja Bele, Jure Acimovic, Martina Perše, Gregor Majdic, Cornelia Prehn, Jerzy Adamski, Damjana RozmanAbstract:The cytochrome P450 (CYP) genes Cyp51, Cyp11a1, CYP17A1, Cyb11b1, Cyp11b2 and Cyp21a1 are involved in the adrenal production of corticosteroids, whose circulating levels are circadian. cAMP signaling plays an important role in adrenal steroidogenesis. By using cAMP responsive element modulator (Crem) knockout mice, we show that CREM isoforms contribute to circadian expression of steroidogenic CYPs in the mouse adrenal gland. Most striking was the CREM-dependent hypomethylation of the CYP17A1 promoter at zeitgeber time 12, which resulted in higher CYP17A1 mRNA and protein expression in the knockout adrenal glands. The data indicate that products of the Crem gene control the epigenetic repression of Cyp17 in mouse adrenal glands.
Kaye L Stenvers - One of the best experts on this subject based on the ideXlab platform.
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fetal testis dysgenesis and compromised leydig cell function in tgfbr3 betaglycan knockout mice
Biology of Reproduction, 2010Co-Authors: Mai A Sarraj, Ruth M Escalona, Alexandra Umbers, Hui Kheng Chua, Chris Small, Michael D Griswold, Kate L Loveland, Jock K Findlay, Kaye L StenversAbstract:Abstract Betaglycan (Tgfbr3) is a coreceptor for transforming growth factor-beta (TGFB) superfamily ligands. In the current study, a defect in seminiferous cord formation was detected in 12.5–13.5 days postcoitum (dpc) betaglycan null murine testis. Immunohistochemistry with antibodies against cell-specific markers revealed defects in somatic cell populations. To confirm these data, quantitative real-time PCR was performed to determine changes in the expression levels of genes involved in fetal testis cell differentiation and function. The expression levels of the Leydig cell markers Insl3, CYP17A1, Cyp11a1, Star, and Hsd3b1 were reduced in knockout testis compared to wild-type testis, beginning at 12.5 dpc. Whole mount in situ hybridization confirmed that Cyp11a1 expression was reduced in the null testis, but its distribution pattern was unchanged. Apoptosis was not affected by the loss of betaglycan, but proliferation within the interstitium was reduced at 14.5 dpc. However, morphometric analysis showed...
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fetal testis dysgenesis and compromised leydig cell function in tgfbr3 betaglycan knockout mice short title phenotype of betaglycan null testis summary sentence the absence of murine tgfbr3 betaglycan causes a disruption to fetal testicular cord stru
2009Co-Authors: Mai A Sarraj, Ruth M Escalona, Alexandra Umbers, Hui Kheng Chua, Chris Small, Kate L Loveland, Jock K Findlay, Kaye L StenversAbstract:Betaglycan (Tgfbr3) is a coreceptor for TGFB superfamily ligands. In the current study, a defect in seminiferous cord formation was detected in 12.5-13.5 dpc betaglycan null murine testis. Immunohistochemistry with antibodies against cell-specific markers revealed defects in somatic cell populations. To confirm these data, quantitative real time PCR was performed to determine changes in the expression levels of genes involved in fetal testis cell differentiation and function. The expression levels of the Leydig cell markers Insl3, CYP17A1, Cyp11a1, Star, and Hsd3b1 were reduced in knockout testis compared to wild-type testis, beginning at 12.5 dpc. Wholemount in situ hybridization confirmed that Cyp11a1 expression was reduced in null testis, but its distribution pattern was unchanged. Apoptosis was not affected by the loss of betaglycan, but proliferation within the interstitium was reduced at 14.5 dpc. However, morphometric analysis showed no changes in Leydig cell counts between the wild-type and the knockout testis at 14.5 dpc, indicating that fetal Leydig function, rather than number, was affected by the loss of betaglycan. The expression levels of Sertoli cell markers Dhh, Sox9, and Amh were also reduced in the knockout testis at 14.5 dpc. However, the expression of fetal germ cell markers Pou5f1 and DDX4 were not changed across the genotypes at any age examined. Our data show that the presence of betaglycan is required for normal cord formation, normal fetal Leydig cell development and the establishment of fetal testis endocrine function, thus implicating TGFB superfamily members as regulators of early fetal testis structure and function.
Mai A Sarraj - One of the best experts on this subject based on the ideXlab platform.
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fetal testis dysgenesis and compromised leydig cell function in tgfbr3 betaglycan knockout mice
Biology of Reproduction, 2010Co-Authors: Mai A Sarraj, Ruth M Escalona, Alexandra Umbers, Hui Kheng Chua, Chris Small, Michael D Griswold, Kate L Loveland, Jock K Findlay, Kaye L StenversAbstract:Abstract Betaglycan (Tgfbr3) is a coreceptor for transforming growth factor-beta (TGFB) superfamily ligands. In the current study, a defect in seminiferous cord formation was detected in 12.5–13.5 days postcoitum (dpc) betaglycan null murine testis. Immunohistochemistry with antibodies against cell-specific markers revealed defects in somatic cell populations. To confirm these data, quantitative real-time PCR was performed to determine changes in the expression levels of genes involved in fetal testis cell differentiation and function. The expression levels of the Leydig cell markers Insl3, CYP17A1, Cyp11a1, Star, and Hsd3b1 were reduced in knockout testis compared to wild-type testis, beginning at 12.5 dpc. Whole mount in situ hybridization confirmed that Cyp11a1 expression was reduced in the null testis, but its distribution pattern was unchanged. Apoptosis was not affected by the loss of betaglycan, but proliferation within the interstitium was reduced at 14.5 dpc. However, morphometric analysis showed...
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fetal testis dysgenesis and compromised leydig cell function in tgfbr3 betaglycan knockout mice short title phenotype of betaglycan null testis summary sentence the absence of murine tgfbr3 betaglycan causes a disruption to fetal testicular cord stru
2009Co-Authors: Mai A Sarraj, Ruth M Escalona, Alexandra Umbers, Hui Kheng Chua, Chris Small, Kate L Loveland, Jock K Findlay, Kaye L StenversAbstract:Betaglycan (Tgfbr3) is a coreceptor for TGFB superfamily ligands. In the current study, a defect in seminiferous cord formation was detected in 12.5-13.5 dpc betaglycan null murine testis. Immunohistochemistry with antibodies against cell-specific markers revealed defects in somatic cell populations. To confirm these data, quantitative real time PCR was performed to determine changes in the expression levels of genes involved in fetal testis cell differentiation and function. The expression levels of the Leydig cell markers Insl3, CYP17A1, Cyp11a1, Star, and Hsd3b1 were reduced in knockout testis compared to wild-type testis, beginning at 12.5 dpc. Wholemount in situ hybridization confirmed that Cyp11a1 expression was reduced in null testis, but its distribution pattern was unchanged. Apoptosis was not affected by the loss of betaglycan, but proliferation within the interstitium was reduced at 14.5 dpc. However, morphometric analysis showed no changes in Leydig cell counts between the wild-type and the knockout testis at 14.5 dpc, indicating that fetal Leydig function, rather than number, was affected by the loss of betaglycan. The expression levels of Sertoli cell markers Dhh, Sox9, and Amh were also reduced in the knockout testis at 14.5 dpc. However, the expression of fetal germ cell markers Pou5f1 and DDX4 were not changed across the genotypes at any age examined. Our data show that the presence of betaglycan is required for normal cord formation, normal fetal Leydig cell development and the establishment of fetal testis endocrine function, thus implicating TGFB superfamily members as regulators of early fetal testis structure and function.
Rok Košir - One of the best experts on this subject based on the ideXlab platform.
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cytochrome p450 metabolism of the post lanosterol intermediates explains enigmas of cholesterol synthesis
Scientific Reports, 2016Co-Authors: Jure Acimovic, Rok Košir, Martina Perše, Sandeep Goyal, Marko Golicnik, Ales Belic, žiga Urlep, Peter F Guengerich, Damjana RozmanAbstract:Cholesterol synthesis is among the oldest metabolic pathways, consisting of the Bloch and Kandutch-Russell branches. Following lanosterol, sterols of both branches are proposed to be dedicated to cholesterol. We challenge this dogma by mathematical modeling and with experimental evidence. It was not possible to explain the sterol profile of testis in cAMP responsive element modulator tau (Crem τ) knockout mice with mathematical models based on textbook pathways of cholesterol synthesis. Our model differs in the inclusion of virtual sterol metabolizing enzymes branching from the pathway. We tested the hypothesis that enzymes from the cytochrome P450 (CYP) superfamily can participate in the catalysis of non-classical reactions. We show that CYP enzymes can metabolize multiple sterols in vitro, establishing novel branching points of cholesterol synthesis. In conclusion, sterols of cholesterol synthesis can be oxidized further to metabolites not dedicated to production of cholesterol. Additionally, CYP7A1, CYP11A1, CYP27A1, and CYP46A1 are parts of a broader cholesterol synthesis network.
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circadian expression of steroidogenic cytochromes p450 in the mouse adrenal gland involvement of camp responsive element modulator in epigenetic regulation of CYP17A1
FEBS Journal, 2012Co-Authors: Rok Košir, Ursula Prosenc Zmrzljak, Tanja Bele, Jure Acimovic, Martina Perše, Gregor Majdic, Cornelia Prehn, Jerzy Adamski, Damjana RozmanAbstract:The cytochrome P450 (CYP) genes Cyp51, Cyp11a1, CYP17A1, Cyb11b1, Cyp11b2 and Cyp21a1 are involved in the adrenal production of corticosteroids, whose circulating levels are circadian. cAMP signaling plays an important role in adrenal steroidogenesis. By using cAMP responsive element modulator (Crem) knockout mice, we show that CREM isoforms contribute to circadian expression of steroidogenic CYPs in the mouse adrenal gland. Most striking was the CREM-dependent hypomethylation of the CYP17A1 promoter at zeitgeber time 12, which resulted in higher CYP17A1 mRNA and protein expression in the knockout adrenal glands. The data indicate that products of the Crem gene control the epigenetic repression of Cyp17 in mouse adrenal glands.
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Circadian expression of steroidogenic cytochromes P450 in the mouse adrenal gland – involvement of cAMP‐responsive element modulator in epigenetic regulation of CYP17A1
The FEBS journal, 2011Co-Authors: Rok Košir, Ursula Prosenc Zmrzljak, Tanja Bele, Jure Acimovic, Martina Perše, Gregor Majdic, Cornelia Prehn, Jerzy Adamski, Damjana RozmanAbstract:The cytochrome P450 (CYP) genes Cyp51, Cyp11a1, CYP17A1, Cyb11b1, Cyp11b2 and Cyp21a1 are involved in the adrenal production of corticosteroids, whose circulating levels are circadian. cAMP signaling plays an important role in adrenal steroidogenesis. By using cAMP responsive element modulator (Crem) knockout mice, we show that CREM isoforms contribute to circadian expression of steroidogenic CYPs in the mouse adrenal gland. Most striking was the CREM-dependent hypomethylation of the CYP17A1 promoter at zeitgeber time 12, which resulted in higher CYP17A1 mRNA and protein expression in the knockout adrenal glands. The data indicate that products of the Crem gene control the epigenetic repression of Cyp17 in mouse adrenal glands.
Philip G. Knight - One of the best experts on this subject based on the ideXlab platform.
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Follicular expression of pro-inflammatory cytokines tumour necrosis factor-α (TNFα), interleukin 6 (IL6) and their receptors in cattle: TNFα, IL6 and macrophages suppress thecal androgen production in vitro.
Reproduction, 2017Co-Authors: Moafaq Samir, Dareen Mattar, Claire Glister, Mhairi Laird, Philip G. KnightAbstract:Pro-inflammatory cytokines secreted by macrophages and other cell-types are implicated as intra-ovarian factors affecting different aspects of ovarian function including follicle and corpus luteum 'turnover', steroidogenesis and angiogenesis. Here, we compared granulosal (GC) and thecal (TC) expression of TNF, IL6 and their receptors (TNFR1, TNFRSF1B, IL6R) during bovine antral follicle development; all five mRNA transcripts were detected in both GC and TC and statistically significant cell-type and follicle stage-related differences were evident. Since few studies have examined cytokine actions on TC steroidogenesis, we cultured TC under conditions that retain a non-luteinized 'follicular' phenotype and treated them with TNFα and IL6 under basal and LH-stimulated conditions. Both TNFα and IL6 suppressed androgen secretion concomitantly with CYP17A1 and LHCGR mRNA expression. In addition, TNFα reduced INSL3, HSD3B1 and NOS3 expression but increased NOS2 expression. IL6 also reduced LHCGR and STAR expression but did not affect HSD3B1, INSL3, NOS2 or NOS3 expression. Since macrophages are a prominent source of these cytokines in vivo we next co-cultured TC with macrophages and observed an abolition of LH-induced androgen production accompanied by a reduction in CYP17A1, INSL3, LHCGR, STAR, CYP11A1 and HSD3B1 expression. Exposure of TC to bacterial lipopolysaccharide also blocked LH-induced androgen secretion, an effect reduced by a toll-like receptor blocker (TAK242). Collectively, the results support an inhibitory action of macrophages on thecal androgen production, likely mediated by their secretion of pro-inflammatory cytokines that downregulate expression of LHCGR, CYP17A1 and INSL3. Bovine theca interna cells can also detect and respond directly to lipopolysaccharide.
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Evidence for an inhibitory role of bone morphogenetic protein(s) in the follicular-luteal transition in cattle.
REPRODUCTION, 2009Co-Authors: Amjad R Kayani, Claire Glister, Philip G. KnightAbstract:Bone morphogenetic proteins (BMPs) and their receptors are expressed in ovarian theca cells (TC) and granulosa cells (GC) and BMPs have been implicated in the regulation of several aspects of follicle development including thecal androgen production and granulosal oestrogen production. Their potential involvement in luteal function has received less attention. In this study, we first compared relative abundance of mRNA transcripts for BMPs, activin-betaA and BMP/activin receptors in bovine corpus luteum (CL) and follicular theca and granulosa layers before undertaking functional in vitro experiments to test the effect of selected ligands (BMP6 and activin A) on luteinizing bovine TC and GC. Relative to beta-actin transcript abundance, CL tissue contained more BMP4 and -6 mRNA than granulosa, more BMP2 mRNA than theca but much less activin-betaA mRNA than both granulosa and theca. Transcripts for all seven BMP/activin receptors were readily detected in each tissue and two transcripts (BMPRII, ActRIIA) were more abundant in CL than either theca or granulosa, consistent with tissue responsiveness. In vitro luteinization of TC and GC from antral follicles (4-6 mm) was achieved by culturing with 5% serum for 6 days. Treatment with BMP6 (0, 2, 10, and 50 ng/ml) and activin A (0, 2, 10 and 50 ng/ml) under these conditions dose-dependently suppressed forskolin-induced progesterone (P4) secretion from both cell types without affecting cell number. BMP6 reduced forskolin-stimulated upregulation of STAR mRNA and raised 'basal' CYP17A1 mRNA level in theca-lutein cells without affecting expression of CYP11A1 or hydroxy-Delta-5-steroid dehydrogenase, 3 beta- and steroid Delta-isomerase 1 (HSD3B1). In granulosa-lutein cells, STAR transcript abundance was not affected by BMP6, whereas forskolin-induced expression of CYP11A1, HSD3B1, CYP19A1 and oxytocin transcripts was reduced. In both cell types, follistatin attenuated the suppressive effect of activin A and BMP6 on forskolin-induced P4 secretion but had no effect alone. Granulosa-lutein cells secreted low levels of endogenous activin A ( approximately 1 ng/ml); BMP6 reduced this, while raising follistatin secretion thus decreasing activin A:follistatin ratio. Collectively, these findings support inhibitory roles for BMP/activin signalling in luteinization and steroidogenesis in both TC and GC.
