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Maria Norlin - One of the best experts on this subject based on the ideXlab platform.
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estrogen mediated regulation of steroid metabolism in rat glial cells effects on neurosteroid levels via regulation of CYP7B1 mediated catalysis
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Grzegorz Wicher, Maria NorlinAbstract:Many neuroactive steroids, including dehydroepiandrosterone (DHEA), pregnenolone, 27-hydroxycholesterol and 17β-estradiol, are known to affect development and function of the brain and nervous system. These and other steroids can undergo tissue and/or cell-specific enzymatic conversions into steroid metabolites. Carefully regulated production of steroids with various physiological effects is important for cells of the nervous system. Astrocytes express many steroidogenic enzymes and are considered important producers of brain steroids. The quantitative roles of different pathways for steroid metabolism in rat astrocytes are not clear. In the current study we examined effects of estrogens on steroid metabolism catalyzed by CYP7B1 and other enzymes in primary cultures of rat astrocytes. The CYP7B1 enzyme, which has been linked to neurodegenerative disease, is involved in the metabolism of several important neurosteroids. In the present study, we found that 7α-hydroxylation, performed by CYP7B1, is the quantitatively most important pathway for DHEA metabolism in rat astrocytes. In addition, our present experiments on catalytic steroid conversions revealed that estrogens significantly suppress the CYP7B1-catalyzed metabolism of not only DHEA but also of pregnenolone and 27-hydroxycholesterol in rat astrocytes. These novel findings point to a regulatory mechanism for control of the cellular levels of these neurosteroids via CYP7B1. Our hypothesis that estrogens can regulate neurosteroid levels via this enzymatic reaction was supported by experiments using ELISA to assay levels of DHEA and pregnenolone in the presence or absence of estrogen. Furthermore, the present results show that estrogen suppresses CYP7B1-catalyzed 7α-hydroxylation also in primary cultures of rat Schwann cells, indicating that regulation by estrogen via this enzyme may be of relevance in both the CNS and the PNS.
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effects of CYP7B1 related steroids on androgen receptor activation in different cell lines
Biochimica et Biophysica Acta, 2012Co-Authors: Johan Lundqvist, Maria NorlinAbstract:The widely expressed steroid hydroxylase CYP7B1 is involved in metabolism of a number of steroids reported to influence estrogen and androgen signaling. Several studies by us and other investigators have linked this enzyme to effects on estrogen receptor activation. In a previous report we examined the effect of CYP7B1-mediated hormone metabolism for estrogen-mediated response in kidney-derived HEK293 cells. In the current study we used an androgen response element (ARE) reporter system to examine androgen-dependent response of some CYP7B1 substrates and CYP7B1-formed metabolites in several cell lines derived from different tissues. The results indicate significantly lower androgen receptor activation by CYP7B1-formed steroid metabolites than by the corresponding steroid substrates, suggesting that CYP7B1-mediated catalysis may decrease some androgenic responses. Thus, CYP7B1-dependent metabolism may be of importance not only for estrogenic signaling but also for androgenic. This finding, that CYP7B1 activity may be a regulator of androgenic signaling by converting AR ligands into less active metabolites, is also supported by real-time RT-PCR experiment where a CYP7B1 substrate, but not the corresponding product, was able to stimulate known androgen-sensitive genes. Furthermore, our data indicate that the effects of some steroids on hormone response element reporter systems are cell line-specific. For instance, despite transfection of the same reporter systems, 5-androstene-3β,17β-diol strongly activates an androgen-dependent response element in prostate cancer cells whereas it elicits only ER-dependent responses in kidney HEK293 cells. Potential roles of cell-specific metabolism or comodulator expression for the observed differences are discussed.
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Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regulation of CYP7B1-mediated metabolism.
Neurochemistry international, 2011Co-Authors: Åsa Fex Svenningsen, Grzegorz Wicher, Johan Lundqvist, Hanna Pettersson, Mikael Corell, Maria NorlinAbstract:The neurosteroid dehydroepiandrosterone (DHEA) is formed locally in the CNS and has been implicated in several processes essential for CNS function, including control of neuronal survival. An important metabolic pathway for DHEA in the CNS involves the steroid hydroxylase CYP7B1. In previous studies, CYP7B1 was identified as a target for estrogen regulation in cells of kidney and liver. In the current study, we examined effects of estrogens on CYP7B1-mediated metabolism of DHEA in primary cultures of rat astrocytes and co-cultures of rat CNS cells. Astrocytes, which interact with neurons in several ways, are important for brain neurosteroidogenesis. We found that estradiol significantly suppressed CYP7B1-mediated DHEA hydroxylation in primary mixed CNS cultures from fetal and newborn rats. Also, CYP7B1-mediated DHEA hydroxylation and CYP7B1 mRNA were markedly suppressed by estrogen in primary cultures of rat astrocytes. Interestingly, diarylpropionitrile, a well-known agonist of estrogen receptor β, also suppressed CYP7B1-mediated hydroxylation of DHEA. Several previous studies have reported neuroprotective effects of estrogens. The current data indicate that one of the mechanisms whereby estrogen can exert protective effects in the CNS may involve increase of the levels of DHEA by suppression of its metabolism.
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effects of CYP7B1 mediated catalysis on estrogen receptor activation
Biochimica et Biophysica Acta, 2010Co-Authors: Hanna Pettersson, Johan Lundqvist, Maria NorlinAbstract:Abstract Most of the many biological effects of estrogens are mediated via the estrogen receptors ERα and β. The current study examines the role of CYP7B1-mediated catalysis for activation of ER. Several reports suggest that CYP7B1 may be important for hormonal action but previously published studies are contradictory concerning the manner in which CYP7B1 affects ERβ-mediated response. In the current study, we examined effects of several CYP7B1-related steroids on ER activation, using an estrogen response element (ERE) reporter system. Our studies showed significant stimulation of ER by 5-androstene-3β,17β-diol (Aene-diol) and 5α-androstane-3β,17β-diol (3β-Adiol). In contrast, the CYP7B1-formed metabolites from these steroids did not activate the receptor, indicating that CYP7B1-mediated metabolism abolishes the ER-stimulating effect of these compounds. The mRNA level of HEM45, a gene known to be stimulated by estrogens, was strongly up-regulated by Aene-diol but not by its CYP7B1-formed metabolite, further supporting this concept. We did not observe stimulation by dehydroepiandrosterone (DHEA) or 7α-hydroxy-DHEA, previously suggested to affect ERβ-mediated response. As part of these studies we examined metabolism of Aene-diol in pig liver which is high in CYP7B1 content. These experiments indicate that CYP7B1-mediated metabolism of Aene-diol is of a similar rate as the metabolism of the well-known CYP7B1 substrates DHEA and 3β-Adiol. CYP7B1-mediated metabolism of 3β-Adiol has been proposed to influence ERβ-mediated growth suppression. Our results indicate that Aene-diol also might be important for ER-related pathways. Our data indicate that low concentrations of Aene-diol can trigger ER-mediated response equally well for both ERα and β and that CYP7B1-mediated conversion of Aene-diol into a 7α-hydroxymetabolite will result in loss of action.
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CYP7B1 mediated metabolism of 5α androstane 3α 17β diol 3α adiol a novel pathway for potential regulation of the cellular levels of androgens and neurosteroids
Biochimica et Biophysica Acta, 2009Co-Authors: Hanna Pettersson, Johan Lundqvist, Ernst H Oliw, Maria NorlinAbstract:Abstract The current study presents data indicating that 5α-androstane-3α,17β-diol (3α-Adiol) undergoes a previously unknown metabolism into hydroxymetabolites, catalyzed by CYP7B1. 3α-Adiol is an androgenic steroid which serves as a source for the potent androgen dihydrotestosterone and also can modulate gamma-amino butyric acid A (GABAA) receptor function in the brain. The steroid hydroxylase CYP7B1 is known to metabolize cholesterol derivatives, sex hormone precursors and certain estrogens, but has previously not been thought to act on androgens or 3α-hydroxylated steroids. 3α-Adiol was found to undergo NADPH-dependent metabolism into 6- and 7-hydroxymetabolites in incubations with porcine microsomes and human kidney-derived HEK293 cells, which are high in CYP7B1 content. This metabolism was suppressed by addition of steroids known to be metabolized by CYP7B1. In addition, 3α-Adiol significantly suppressed CYP7B1-mediated catalytic reactions, in a way as would be expected for substrates that compete for the same enzyme. Recombinant expression of human CYP7B1 in HEK293 cells significantly increased the rate of 3α-Adiol hydroxylation. Furthermore, the observed hydroxylase activity towards 3α-Adiol was very low or undetectable in livers of CYP7B1(−/−) knockout mice. The present results indicate that CYP7B1-mediated catalysis may play a role for control of the cellular levels of androgens, not only of estrogens. These findings suggest a previously unknown mechanism for metabolic elimination of 3α-Adiol which may impact intracellular levels of dihydrotestosterone and GABAA-modulating steroids.
Filippo M. Santorelli - One of the best experts on this subject based on the ideXlab platform.
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White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1
Neuromuscular disorders : NMD, 2009Co-Authors: Roberta Biancheri, Marianna Ciccolella, Andrea Rossi, Alessandra Tessa, Denise Cassandrini, C. Minetti, Filippo M. SantorelliAbstract:Hereditary spastic paraplegias (HSPs) are relatively frequent disorders presenting great genetic heterogeneity. The recent identification of mutations in SPG5/CYP7B1 in six autosomal recessive kindred linked to the SPG5 locus on chromosome 8q prompted us to test the relative frequency of SPG5/CYP7B1 variants in 12 families and in sporadic HSP patients by high-resolution melting screening combined with direct sequencing. We present two patients who harbored three mutations (including two novel variants) in SPG5/CYP7B1 and white matter involvement evidenced at brain MRI. In HSP patients in whom no other genes were mutated, screening of SPG5/CYP7B1 seems to have a low diagnostic yield in autosomal recessive (8%) and sporadic (
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white matter lesions in spastic paraplegia with mutations in spg5 CYP7B1
Neuromuscular Disorders, 2009Co-Authors: Roberta Biancheri, Marianna Ciccolella, Andrea Rossi, Alessandra Tessa, Denise Cassandrini, C. Minetti, Filippo M. SantorelliAbstract:Hereditary spastic paraplegias (HSPs) are relatively frequent disorders presenting great genetic heterogeneity. The recent identification of mutations in SPG5/CYP7B1 in six autosomal recessive kindred linked to the SPG5 locus on chromosome 8q prompted us to test the relative frequency of SPG5/CYP7B1 variants in 12 families and in sporadic HSP patients by high-resolution melting screening combined with direct sequencing. We present two patients who harbored three mutations (including two novel variants) in SPG5/CYP7B1 and white matter involvement evidenced at brain MRI. In HSP patients in whom no other genes were mutated, screening of SPG5/CYP7B1 seems to have a low diagnostic yield in autosomal recessive (8%) and sporadic (<1%) cases, even in those with complicated clinical features.
Nereo Bresolin - One of the best experts on this subject based on the ideXlab platform.
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clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations
Clinical Genetics, 2012Co-Authors: Alessia Arnoldi, Marina Scarlato, Olimpia Musumeci, Antonio Toscano, Claudia Crimella, Erika Tenderini, Andrea Martinuzzi, M G Dangelo, Marianna Fantin, Nereo BresolinAbstract:Arnoldi A, Crimella C, Tenderini E, Martinuzzi A, D’Angelo MG, Musumeci O, Toscano A, Scarlato M, Fantin M, Bresolin N, Bassi MT. Clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations. Spastic paraplegia type 5 (SPG5) is caused by mutations in CYP7B1, a gene encoding the cytochrome P-450 oxysterol 7-α-hydroxylase, CYP7B1, an enzyme implicated in the cholesterol metabolism. Mutations in CYP7B1 were found in both pure and complicated forms of the disease with a mutation frequency of 7.7% in pure recessive cases. The mutation frequency in complex forms, approximately 6.6%, is more controversial and needs to be refined. We studied in more detail the SPG5-related spectrum of complex phenotypes by screening CYPB1 for mutations in a large cohort of 105 Italian hereditary spastic paraplegias (HSPs) index patients including 50 patients with a complicated HSP (cHSP) phenotype overlapping the SPG11- and the SPG15-related forms except for the lack of thin corpus callosum and 55 pure patients. Five CYP7B1 mutations, three of which are novel, were identified in four patients, two with a complex form of the disease and two with a pure phenotype. The CYP7B1 mutation frequencies obtained in both complicated and pure familial cases are comparable to the known ones. These results obtained extend the range of SPG5-related phenotypes and reveal variability in clinical presentation, disease course and functional profile in the SPG5-related patients while providing with some clues for molecular diagnosis in cHSP.
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clinical phenotype variability in patients with hereditary spastic paraplegia type 5 associated with CYP7B1 mutations
Clinical Genetics, 2012Co-Authors: Alessia Arnoldi, Marina Scarlato, Olimpia Musumeci, Antonio Toscano, Claudia Crimella, Erika Tenderini, Andrea Martinuzzi, M G Dangelo, Marianna Fantin, Nereo BresolinAbstract:Spastic paraplegia type 5 (SPG5) is caused by mutations in CYP7B1, a gene encoding the cytochrome P-450 oxysterol 7-α-hydroxylase, CYP7B1, an enzyme implicated in the cholesterol metabolism. Mutations in CYP7B1 were found in both pure and complicated forms of the disease with a mutation frequency of 7.7% in pure recessive cases. The mutation frequency in complex forms, approximately 6.6%, is more controversial and needs to be refined. We studied in more detail the SPG5-related spectrum of complex phenotypes by screening CYPB1 for mutations in a large cohort of 105 Italian hereditary spastic paraplegias (HSPs) index patients including 50 patients with a complicated HSP (cHSP) phenotype overlapping the SPG11- and the SPG15-related forms except for the lack of thin corpus callosum and 55 pure patients. Five CYP7B1 mutations, three of which are novel, were identified in four patients, two with a complex form of the disease and two with a pure phenotype. The CYP7B1 mutation frequencies obtained in both complicated and pure familial cases are comparable to the known ones. These results obtained extend the range of SPG5-related phenotypes and reveal variability in clinical presentation, disease course and functional profile in the SPG5-related patients while providing with some clues for molecular diagnosis in cHSP.
Anton M Jetten - One of the best experts on this subject based on the ideXlab platform.
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identification of oxysterol 7α hydroxylase CYP7B1 as a novel retinoid related orphan receptor α rorα nr1f1 target gene and a functional cross talk between rorα and liver x receptor nr1h3
Molecular Pharmacology, 2008Co-Authors: Taira Wada, Ewa Ellis, Hong Soon Kang, Martin Angers, Haibiao Gong, Shikha Bhatia, Shaheen Khadem, Songrong Ren, Stephen C Strom, Anton M JettenAbstract:The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORalpha (NR1F1) in regulating the oxysterol 7alpha-hydroxylase (CYP7B1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of CYP7B1 gene was suppressed in the RORalpha null (RORalpha(sg/sg)) mice, suggesting RORalpha as a positive regulator of CYP7B1. Promoter analysis established CYP7B1 as a transcriptional target of RORalpha, and transfection of RORalpha induced the expression of endogenous CYP7B1 in the liver. Interestingly, CYP7B1 regulation seemed to be RORalpha-specific, because RORgamma had little effect. Reporter gene analysis showed that the activation of CYP7B1 gene promoter by RORalpha was suppressed by LXRalpha (NR1H3), whereas RORalpha inhibited both the constitutive and ligand-dependent activities of LXRalpha. The mutual suppression between RORalpha and LXR was supported by the in vivo observation that loss of RORalpha increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR alpha and beta isoforms showed activation of selected RORalpha target genes. Our results have revealed a novel role for RORalpha and a functional interplay between RORalpha and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis.
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identification of oxysterol 7α hydroxylase CYP7B1 as a novel retinoid related orphan receptor α rorα nr1f1 target gene and a functional cross talk between rorα and liver x receptor nr1h3
Molecular Pharmacology, 2008Co-Authors: Taira Wada, Ewa Ellis, Hong Soon Kang, Martin Angers, Haibiao Gong, Shikha Bhatia, Shaheen Khadem, Songrong Ren, Stephen C Strom, Anton M JettenAbstract:The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of RORα (NR1F1) in regulating the oxysterol 7α-hydroxylase (CYP7B1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of CYP7B1 gene was suppressed in the RORα null (RORαsg/sg) mice, suggesting RORα as a positive regulator of CYP7B1. Promoter analysis established CYP7B1 as a transcriptional target of RORα, and transfection of RORα induced the expression of endogenous CYP7B1 in the liver. Interestingly, CYP7B1 regulation seemed to be RORα-specific, because RORγ had little effect. Reporter gene analysis showed that the activation of CYP7B1 gene promoter by RORα was suppressed by LXRα (NR1H3), whereas RORα inhibited both the constitutive and ligand-dependent activities of LXRα. The mutual suppression between RORα and LXR was supported by the in vivo observation that loss of RORα increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR α and β isoforms showed activation of selected RORα target genes. Our results have revealed a novel role for RORα and a functional interplay between RORα and LXR in regulating endo- and xenobiotic genes, which may have broad implications in metabolic homeostasis.
Roberta Biancheri - One of the best experts on this subject based on the ideXlab platform.
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White matter lesions in spastic paraplegia with mutations in SPG5/CYP7B1
Neuromuscular disorders : NMD, 2009Co-Authors: Roberta Biancheri, Marianna Ciccolella, Andrea Rossi, Alessandra Tessa, Denise Cassandrini, C. Minetti, Filippo M. SantorelliAbstract:Hereditary spastic paraplegias (HSPs) are relatively frequent disorders presenting great genetic heterogeneity. The recent identification of mutations in SPG5/CYP7B1 in six autosomal recessive kindred linked to the SPG5 locus on chromosome 8q prompted us to test the relative frequency of SPG5/CYP7B1 variants in 12 families and in sporadic HSP patients by high-resolution melting screening combined with direct sequencing. We present two patients who harbored three mutations (including two novel variants) in SPG5/CYP7B1 and white matter involvement evidenced at brain MRI. In HSP patients in whom no other genes were mutated, screening of SPG5/CYP7B1 seems to have a low diagnostic yield in autosomal recessive (8%) and sporadic (
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white matter lesions in spastic paraplegia with mutations in spg5 CYP7B1
Neuromuscular Disorders, 2009Co-Authors: Roberta Biancheri, Marianna Ciccolella, Andrea Rossi, Alessandra Tessa, Denise Cassandrini, C. Minetti, Filippo M. SantorelliAbstract:Hereditary spastic paraplegias (HSPs) are relatively frequent disorders presenting great genetic heterogeneity. The recent identification of mutations in SPG5/CYP7B1 in six autosomal recessive kindred linked to the SPG5 locus on chromosome 8q prompted us to test the relative frequency of SPG5/CYP7B1 variants in 12 families and in sporadic HSP patients by high-resolution melting screening combined with direct sequencing. We present two patients who harbored three mutations (including two novel variants) in SPG5/CYP7B1 and white matter involvement evidenced at brain MRI. In HSP patients in whom no other genes were mutated, screening of SPG5/CYP7B1 seems to have a low diagnostic yield in autosomal recessive (8%) and sporadic (<1%) cases, even in those with complicated clinical features.
