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Masahiko Negishi - One of the best experts on this subject based on the ideXlab platform.
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Nuclear receptor CAR-ERα signaling regulates the Estrogen Sulfotransferase gene in the liver.
Scientific reports, 2020Co-Authors: Muluneh Fashe, Rick Moore, Shingo Arakawa, Tatsuya Sueyoshi, Masahiko NegishiAbstract:Estrogen Sulfotransferase (SULT1E1) inactivates Estrogen and regulates its metabolic homeostats. Whereas SULT1E1 is expressed low in the liver of adult mice, it is induced by phenobarbital (PB) treatment or spontaneously in diabetic livers via nuclear receptors. Utilizing constitutive active/androstane receptor (CAR) KO, Estrogen receptor α (ERα KO, phosphorylation-blocked ERα S216A KI mice, it is now demonstrated that, after being activated by PB, CAR binds and recruits ERα onto the Sulte1 promoter for subsequent phosphorylation at Ser216. This phosphorylation tightens CAR interacting with ERα and to activates the promoter. Hepatic SULT1E1 mRNA levels are constitutively up-regulated in type 1 diabetic Akita mice; CAR spontaneously accumulates in the nucleus and activates the Sult1e1 promoter by recruiting phosphorylated ERα in the liver as observed with PB-induced livers. Thus, this CAR-phosphorylated ERα signaling enables these two nuclear receptors to communicate, activating the Sult1e1 gene in response to either PB or diabetes in mice. ERα phosphorylation may integrate CAR into Estrogen actions, providing insights into understanding drug-hormone interactions in clinical therapy.
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phenobarbital induced phosphorylation converts nuclear receptor rorα from a repressor to an activator of the Estrogen Sulfotransferase gene sult1e1 in mouse livers
FEBS Letters, 2018Co-Authors: Muluneh Fashe, Myeongjin Yi, Rick Moore, Takuyu Hashiguchi, Masahiko NegishiAbstract:: The Estrogen Sulfotransferase SULT1E1 sulfates and inactivates Estrogen, which is reactivated via desulfation by steroid sulfatase, thus regulating Estrogen homeostasis. Phenobarbital (PB), a clinical sedative, activates Sult1e1 gene transcription in mouse livers. Here, the molecular mechanism by which the nuclear receptors CAR, which is targeted by PB, and RORα communicate through phosphorylation to regulate Sult1e1 activation has been studied. RORα, a basal activity repressor of the Sult1e1 promoter, becomes phosphorylated at serine 100 and converts to an activator of the Sult1e1 promoter in response to PB. CAR regulates both the RORα phosphorylation and conversion. Our findings suggest that PB signals CAR to communicate with RORα via serine 100 phosphorylation, converting RORα from transcription repressor to activator of the Sult1e1 gene and inducing SULT1E1 expression in mouse livers.
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Crystallographic analysis of a hydroxylated polychlorinated biphenyl (OH-PCB) bound to the catalytic Estrogen binding site of human Estrogen Sulfotransferase.
Environmental health perspectives, 2003Co-Authors: Sergei Shevtsov, Evgeniy V. Petrotchenko, Lars C. Pedersen, Masahiko NegishiAbstract:Certain hydroxylated polychlorinated biphenyls (OH-PCBs) inhibit the human Estrogen Sulfotransferase (hEST) at subnanomolar concentrations, suggesting a possible pathway for PCB toxicity due to env...
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Substrate Gating Confers Steroid Specificity to Estrogen Sulfotransferase
The Journal of biological chemistry, 1999Co-Authors: Evgeniy V. Petrotchenko, Lars C. Pedersen, Mary E. Doerflein, Yoshimitsu Kakuta, Masahiko NegishiAbstract:Abstract Estrogen Sulfotransferase (EST) exhibits a high substrate specificity and catalytic efficiency toward Estrogens such as estradiol (E2) but insignificant ability to sulfate hydroxysteroids such as dehydroepiandrosterone (DHEA). To provide the structural basis for this Estrogen specificity, we mutated amino acid residues that constitute the substrate-binding site of EST. Among these mutants, only Tyr-81 decreased E2 and increased DHEA Sulfotransferase activities. Substitution for Tyr-81 by smaller hydrophobic residues increasedK m (E2) for E2 activity, whereas thek cat(E2) remained relatively constant. The Y81L mutant exhibited the same DHEA activity as wild-type hydroxysteroid Sulfotransferase, for whichK m (DHEA) remained relatively constant, and k cat(DHEA) was markedly increased. The side chain of Tyr-81 is directed at the A-ring of the E2 molecule in the substrate-binding pocket of EST, constituting a steric gate with Phe-142 sandwiching E2 from the opposite side. The present mutagenesis study indicates that the 3β-hydroxyl group of the DHEA molecule is excluded from the catalytic site of EST through steric hindrance of Tyr-81 with the C-19 methyl group of DHEA. Thus, this stricture-like gating caused by steric hindrance appears to be a structural principle for conferring Estrogen specificity to EST.
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Cellular Localization and Regulation of Expression of Testicular Estrogen Sulfotransferase
Endocrinology, 1997Co-Authors: Wen Chao Song, Yueming Qian, Xiujun Sun, Masahiko NegishiAbstract:Estrogen Sulfotransferase (EST) is a cytosolic enzyme that catalyzes the specific sulfonation of Estrogens at the 3-hydroxyl position using 3′-phosphoadenosine-5′-phosphosulfate as an activated sulfate donor. Sulfated Estrogens no longer bind to the Estrogen receptor and are, therefore, hormonally inactive. Although liver has been considered a primary site for steroid Sulfotransferase activities, we previously have cloned the mouse EST complementary DNA and found the enzyme to be expressed abundantly in the testis of normal mice. In this study we show by reverse transcription-PCR that EST is also expressed in the testes of rat and man, suggesting that testicular expression of EST may be a common phenomenon among different species. Using a purified polyclonal antibody raised against the bacterially expressed mouse EST protein, we demonstrate by immunohistochemistry that EST is localized selectively to the androgen-producing Leydig cells within the mouse testis. Additionally, we show that Leydig cell expres...
Charles A. Strott - One of the best experts on this subject based on the ideXlab platform.
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Proposed active site domain in Estrogen Sulfotransferase as determined by mutational analysis
Proceedings of the National Academy of Sciences of the United States of America, 1995Co-Authors: William J. Driscoll, Katsutoshi Komatsu, Charles A. StrottAbstract:Abstract Point mutations were selectively introduced into a cDNA for guinea pig Estrogen Sulfotransferase (gpEST); each construct was then expressed in Chinese hamster ovary K1 cells. The molecular site chosen for study is a conserved GXXGXXK sequence that resembles the P-loop-type nucleotide-binding motif for ATP- and GTP-binding proteins and is located near the C terminus of all steroid and phenol(aryl) Sulfotransferases for which the primary structures are known. Preliminary experiments demonstrated that the GXXGXXK motif is essential for binding the activated sulfonate donor 3'-phosphoadenosine 5'-phosphosulfate (PAPS). The present study was undertaken to ascertain the relative importance of each individual residue of the motif. While the mutation of a single motif residue had little effect on the interaction between gpEST and PAPS as determined by kinetic analysis and photoaffinity labeling, the mutation of any two residues in concert resulted in an approximate 10-fold increase in the Km for PAPS and reduced photoaffinity labeling. The mutation of all three motif residues resulted in an inactive enzyme and complete loss of photoaffinity labeling. Interestingly, several mutants also displayed a striking effect on the Km for the steroid substrate; double mutants, again, demonstrated greater perturbations (8- to 28-fold increase) than did single mutants. Unexpectedly, whereas the mutation of nonmotif residues had a negligible effect on the Km for PAPS, a marked increase in the Km for the Estrogen substrate ( > 30-fold) was noted. On the basis of these findings, it is concluded that the sequence GISGDWKN within the C-terminal domain of gpEST represents a critical component of the active site.
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Adrenocortical pregnenolone binding activity resides with Estrogen Sulfotransferase.
Endocrinology, 1995Co-Authors: Ying-hue Lee, Chang-shin Park, K. Komatsu, J. Kwack, Charles A. StrottAbstract:Cytosol prepared from Chinese hamster ovary (CHO)-K1 cells transfected with guinea pig Estrogen Sulfotransferase (EST) cDNA demonstrated high affinity binding activity for pregnenolone as well as 17 beta-estradiol but failed to bind dehydroepiandrosterone or testosterone. In contrast, cytosol prepared from nontransfected CHO-K1 cells did not demonstrate steroid binding activity. Additionally, the binding activity for pregnenolone and 17 beta-estradiol was dependent on the presence of the cofactor adenosine-3',5'-diphosphate. Pregnenolone and 17 beta-estradiol effectively competed with each other for binding. On the other hand, pregnenolone, which was not sulfonated, did not inhibit the sulfonation of 17 beta-estradiol by expressed EST.
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Characterization of Guinea Pig Estrogen Sulfotransferase Expressed by Chinese Hamster Ovary Cell-K1 Stable Transfectants
Endocrinology, 1994Co-Authors: Takuya Tomizuka, Toru Oeda, Yasushi Tamura, Sho Yoshida, Charles A. StrottAbstract:Estrogen Sulfotransferase (EST) activity expressed by Chinese hamster ovary (CHO)-K1 cells stably transfected with a plasmid containing a guinea pig EST complementary DNA insert was subjected to biochemical characterization, and the EST protein was further examined by nondenaturing isoelectric focusing and immunoblot analysis. CHO-K1 cells transfected with the same plasmid without the EST complementary DNA insert as well as untransfected CHO-K1 cells did not demonstrate either EST activity or the presence of an immunologically related protein. The EST expressed by the stably transfected CHO-K1 cells was found to manifest Michaelis-Menten kinetics and would use only Estrogenic steroids as substrates, whereas other forms of steroids, such as pregnenolone, dehydroepiandrosterone, cortisol, and testosterone, were not acted on. When 17 beta-estradiol was used as a substrate, sulfonation occurred exclusively at the 3 position; 17-sulfonate was not formed. Thus, the expressed EST acted selectively on the 3-hydro...
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Cloning and Sequence Analysis of the 5′-Flanking Region of the Estrogen Sulfotransferase Gene: Steroid Response Elements and Cell-Specific Nuclear DNA-Binding Proteins
Biochemical and biophysical research communications, 1993Co-Authors: K. Komatsu, T. Oeda, Charles A. StrottAbstract:Abstract A 2954 bp region of the guinea pig Estrogen Sulfotransferase gene was cloned and sequenced including 2888 nt upstream of the cap site. This represents the first cloning of the promoter region of a steroid Sulfotransferase gene. The 5′-flanking region was found to contain a conventional TATA box variant and sequences homologous to Estrogen and glucocorticoid response elements. Gel mobility shift assays detected the presence of nuclear proteins in adrenocortical SW-13 and Y-1 cells that bind specifically to 30 mer DNA sequences containing either Estrogen or glucocorticoid response elements. In contrast, gel shift experiments using 3T3 fibrolast cells failed to demonstrate similarly upshifted bands. Block deletion studies indicated that regulation of basal Estrogen Sulfotransferase promoter activity was located within the first 1000 bp upstream of the transcription initiation site.
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cloning and sequence analysis of the 5 flanking region of the Estrogen Sulfotransferase gene steroid response elements and cell specific nuclear dna binding proteins
Biochemical and Biophysical Research Communications, 1993Co-Authors: K. Komatsu, T. Oeda, Charles A. StrottAbstract:Abstract A 2954 bp region of the guinea pig Estrogen Sulfotransferase gene was cloned and sequenced including 2888 nt upstream of the cap site. This represents the first cloning of the promoter region of a steroid Sulfotransferase gene. The 5′-flanking region was found to contain a conventional TATA box variant and sequences homologous to Estrogen and glucocorticoid response elements. Gel mobility shift assays detected the presence of nuclear proteins in adrenocortical SW-13 and Y-1 cells that bind specifically to 30 mer DNA sequences containing either Estrogen or glucocorticoid response elements. In contrast, gel shift experiments using 3T3 fibrolast cells failed to demonstrate similarly upshifted bands. Block deletion studies indicated that regulation of basal Estrogen Sulfotransferase promoter activity was located within the first 1000 bp upstream of the transcription initiation site.
Wen Chao Song - One of the best experts on this subject based on the ideXlab platform.
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hepatic Estrogen Sulfotransferase distantly sensitizes mice to hemorrhagic shock induced acute lung injury
Endocrinology, 2020Co-Authors: Yang Xie, Wen Chao Song, Robert B Gibbs, Anne Caroline S Barbosa, Patrick J Oberly, Songrong Ren, Samuel M Poloyac, Jie Fan, Wen XieAbstract:Hemorrhagic shock (HS) is a potential life-threatening condition that may lead to injury to multiple organs, including the lung. The Estrogen Sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates Estrogens. In this report, we showed that the expression of Est was markedly induced in the liver but not in the lung of female mice subject to HS and resuscitation. Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury (ALI), including interstitial edema, neutrophil mobilization and infiltration, and inflammation. The pulmonoprotective effect of Est ablation or inhibition was sex-specific, because the HS-induced ALI was not affected in male Est-/- mice. Mechanistically, the pulmonoprotective phenotype in female Est-/- mice was accompanied by increased lung and circulating levels of Estrogens, attenuated pulmonary inflammation, and inhibition of neutrophil mobilization from the bone marrow and neutrophil infiltration to the lung, whereas the pulmonoprotective effect was abolished upon ovariectomy, suggesting that the protection was Estrogen dependent. The pulmonoprotective effect of Est ablation was also tissue specific, as loss of Est had little effect on HS-induced liver injury. Moreover, transgenic reconstitution of human EST in the liver of global Est-/- mice abolished the pulmonoprotective effect, suggesting that it is the EST in the liver that sensitizes mice to HS-induced ALI. Taken together, our results revealed a sex- and tissue-specific role of EST in HS-induced ALI. Pharmacological inhibition of EST may represent an effective approach to manage HS-induced ALI.
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Estrogen Sulfotransferase regulates body fat and glucose homeostasis in female mice
American journal of physiology. Endocrinology and metabolism, 2010Co-Authors: Victor K. Khor, Ravindra Dhir, Xiaoyan Yin, Rexford S. Ahima, Wen Chao SongAbstract:Estrogen regulates fat mass and distribution and glucose metabolism. We have previously found that Estrogen Sulfotransferase (EST), which inactivates Estrogen through sulfoconjugation, was highly expressed in adipose tissue of male mice and induced by testosterone in female mice. To determine whether inhibition of Estrogen in female adipose tissue affects adipose mass and metabolism, we generated transgenic mice expressing EST via the aP2 promoter. As expected, EST expression was increased in adipose tissue as well as macrophages. Parametrial and subcutaneous inguinal adipose mass and adipocyte size were significantly reduced in EST transgenic mice, but there was no change in retroperitoneal or brown adipose tissue. EST overexpression decreased the differentiation of primary adipocytes, and this was associated with reductions in the expression of peroxisome proliferator-activated receptor-γ, fatty acid synthase, hormone-sensitive lipase, lipoprotein lipase, and leptin. Serum leptin levels were significantly lower in EST transgenic mice, whereas total and high-molecular-weight adiponectin levels were not different in transgenic and wild-type mice. Glucose uptake was blunted in parametrial adipose tissue during hyperinsulinemic-euglycemic clamp in EST transgenic mice. In contrast, hepatic insulin sensitivity was improved but muscle insulin sensitivity did not change in EST transgenic mice. These results reveal novel effects of EST on adipose tissue and glucose homeostasis in female mice.
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glucocorticoids antagonize Estrogens by glucocorticoid receptor mediated activation of Estrogen Sulfotransferase
Cancer Research, 2008Co-Authors: Haibiao Gong, Michael J. Jarzynka, Taira Wada, Wen Chao Song, Donald B. Defranco, Tim J. Cole, Bin Zhang, Jie Gao, Jung Hoon Lee, Shi Yuan ChengAbstract:Glucocorticoids and Estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate Estrogen responses, but the mechanism by which glucocorticoids inhibit Estrogenic activity is unknown. In this study, we show that activation of glucocorticoid receptor (GR) by dexamethasone (DEX) induced the expression and activity of Estrogen Sulfotransferase (SULT1E1 or EST), an enzyme important for the metabolic deactivation of Estrogens, because sulfonated Estrogens fail to activate the Estrogen receptor. Treatment with DEX lowered circulating Estrogens, compromised uterine Estrogen responses, and inhibited Estrogen-dependent breast cancer growth in vitro and in a xenograft model. We further showed that the mouse and human SULT1E1 genes are transcriptional targets of GR and deletion of Sult1e1/Est in mice abolished the DEX effect on Estrogen responses. These findings have revealed a novel nuclear receptor-mediated and metabolism-based mechanism of Estrogen deprivation, which may have implications in therapeutic development for breast cancers. Because glucocorticoids and Estrogens are widely prescribed drugs, our results also urge caution in avoiding glucocorticoid-Estrogen interactions in patients.
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Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor–Mediated Activation of Estrogen Sulfotransferase
Cancer Research, 2008Co-Authors: Haibiao Gong, Michael J. Jarzynka, Taira Wada, Wen Chao Song, Donald B. Defranco, Tim J. Cole, Bin Zhang, Shi Yuan ChengAbstract:Glucocorticoids and Estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate Estrogen responses, but the mechanism by which glucocorticoids inhibit Estrogenic activity is unknown. In this study, we show that activation of glucocorticoid receptor (GR) by dexamethasone (DEX) induced the expression and activity of Estrogen Sulfotransferase (SULT1E1 or EST), an enzyme important for the metabolic deactivation of Estrogens, because sulfonated Estrogens fail to activate the Estrogen receptor. Treatment with DEX lowered circulating Estrogens, compromised uterine Estrogen responses, and inhibited Estrogen-dependent breast cancer growth in vitro and in a xenograft model. We further showed that the mouse and human SULT1E1 genes are transcriptional targets of GR and deletion of Sult1e1/Est in mice abolished the DEX effect on Estrogen responses. These findings have revealed a novel nuclear receptor–mediated and metabolism-based mechanism of Estrogen deprivation, which may have implications in therapeutic development for breast cancers. Because glucocorticoids and Estrogens are widely prescribed drugs, our results also urge caution in avoiding glucocorticoid-Estrogen interactions in patients. [Cancer Res 2008;68(18):7386–93]
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Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor–Mediated Activation of Estrogen Sulfotransferase
Cancer research, 2008Co-Authors: Haibiao Gong, Michael J. Jarzynka, Taira Wada, Wen Chao Song, Donald B. Defranco, Tim J. Cole, Bin Zhang, Jie Gao, Jung Hoon Lee, Shi Yuan ChengAbstract:Glucocorticoids and Estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate Estrogen responses, but the mechanism by which glucocorticoids inhibit Estrogenic activity is unknown. In this study, we show that activation of glucocorticoid receptor (GR) by dexamethasone (DEX) induced the expression and activity of Estrogen Sulfotransferase (SULT1E1 or EST), an enzyme important for the metabolic deactivation of Estrogens, because sulfonated Estrogens fail to activate the Estrogen receptor. Treatment with DEX lowered circulating Estrogens, compromised uterine Estrogen responses, and inhibited Estrogen-dependent breast cancer growth in vitro and in a xenograft model. We further showed that the mouse and human SULT1E1 genes are transcriptional targets of GR and deletion of Sult1e1/Est in mice abolished the DEX effect on Estrogen responses. These findings have revealed a novel nuclear receptor-mediated and metabolism-based mechanism of Estrogen deprivation, which may have implications in therapeutic development for breast cancers. Because glucocorticoids and Estrogens are widely prescribed drugs, our results also urge caution in avoiding glucocorticoid-Estrogen interactions in patients.
Wen Xie - One of the best experts on this subject based on the ideXlab platform.
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hepatic Estrogen Sulfotransferase distantly sensitizes mice to hemorrhagic shock induced acute lung injury
Endocrinology, 2020Co-Authors: Yang Xie, Wen Chao Song, Robert B Gibbs, Anne Caroline S Barbosa, Patrick J Oberly, Songrong Ren, Samuel M Poloyac, Jie Fan, Wen XieAbstract:Hemorrhagic shock (HS) is a potential life-threatening condition that may lead to injury to multiple organs, including the lung. The Estrogen Sulfotransferase (EST, or SULT1E1) is a conjugating enzyme that sulfonates and deactivates Estrogens. In this report, we showed that the expression of Est was markedly induced in the liver but not in the lung of female mice subject to HS and resuscitation. Genetic ablation or pharmacological inhibition of Est effectively protected female mice from HS-induced acute lung injury (ALI), including interstitial edema, neutrophil mobilization and infiltration, and inflammation. The pulmonoprotective effect of Est ablation or inhibition was sex-specific, because the HS-induced ALI was not affected in male Est-/- mice. Mechanistically, the pulmonoprotective phenotype in female Est-/- mice was accompanied by increased lung and circulating levels of Estrogens, attenuated pulmonary inflammation, and inhibition of neutrophil mobilization from the bone marrow and neutrophil infiltration to the lung, whereas the pulmonoprotective effect was abolished upon ovariectomy, suggesting that the protection was Estrogen dependent. The pulmonoprotective effect of Est ablation was also tissue specific, as loss of Est had little effect on HS-induced liver injury. Moreover, transgenic reconstitution of human EST in the liver of global Est-/- mice abolished the pulmonoprotective effect, suggesting that it is the EST in the liver that sensitizes mice to HS-induced ALI. Taken together, our results revealed a sex- and tissue-specific role of EST in HS-induced ALI. Pharmacological inhibition of EST may represent an effective approach to manage HS-induced ALI.
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Estrogen Sulfotransferase in the metabolism of Estrogenic drugs and in the pathogenesis of diseases.
Expert opinion on drug metabolism & toxicology, 2019Co-Authors: Anne Caroline S Barbosa, Ye Feng, Min Huang, Wen XieAbstract:ABSTRACTIntroduction: Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen Sulfotransferase...
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Sex-Dependent Role of Estrogen Sulfotransferase and Steroid Sulfatase in Metabolic Homeostasis.
Advances in experimental medicine and biology, 2017Co-Authors: Wojciech G. Garbacz, Mengxi Jiang, Wen XieAbstract:Sulfonation and desulfation are two opposing processes that represent an important layer of regulation of Estrogenic activity via ligand supplies. Enzymatic activities of families of enzymes, known as Sulfotransferases and sulfatases, lead to structural and functional changes of the steroids, thyroids, xenobiotics, and neurotransmitters. Estrogen Sulfotransferase (EST) and steroid sulfatase (STS) represent negative and positive regulation of the Estrogen activity, respectively. This is because EST-mediated sulfation deactivates Estrogens, whereas STS-mediated desulfation converts the inactive Estrogen sulfates to active Estrogens. In addition to the known functions of Estrogens, EST and STS in reproductive processes, regulation of Estrogens and other signal molecules especially at the local tissue levels has gained increased attention in the context of metabolic disease in recent years. EST expression is detectable in the subcutaneous adipose tissue in both obese women and men, and the expression of EST is markedly induced in the livers of rodent models of obesity and type 2 diabetes. STS was found to be upregulated in patients with chronic inflammatory liver diseases. Interestingly, the tissue distribution and the transcriptional regulation of EST and STS exhibit obvious sex and species specificity. EST ablation produces completely opposite metabolic phenotype in female and male obese mice. Adipogenesis is also differentially regulated by EST in murine and human adipocytes. This chapter focuses on the recent progress in our understanding of the expression and regulation EST and STS in the context of metabolic homeostasis.
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Sex- and Tissue-Specific Role of Estrogen Sulfotransferase in Energy Homeostasis and Insulin Sensitivity.
Endocrinology, 2017Co-Authors: Wojciech G. Garbacz, Mengxi Jiang, Jun Yamauchi, H. Henry Dong, Wen XieAbstract:Estrogen Sulfotransferase catalyzes the sulfoconjugation and deactivation of Estrogens. Previously, we showed that loss of Est in male ob/ob mice, but not in female ob/ob mice, exacerbated the diabetic phenotype, but the underlying mechanism was unclear. In this study, we show that transgenic reconstitution of Est in the adipose tissue, but not in the liver, attenuated diabetic phenotype in Est-deficient ob/ob mice (obe mice). Mechanistically, adipose reconstitution of Est in obe mice (oae mice) resulted in reduced local and systemic inflammation, improved insulin sensitivity, and increased energy expenditure. At the molecular level, adipose induction of lipocalin-2 (Lcn2) in oae males may have contributed to the inhibition of inflammation because the level of Lcn2 was negatively associated with tumor necrosis factor (Tnf) α expression, and treatment of differentiated adipocytes with Lcn2 antagonized Tnfα-responsive inhibition of insulin signaling. The metabolic benefit of adipose reconstitution of Est was sex specific, because adipose reconstitution of Est in obe females had little effect. Interestingly, despite their improved metabolic functions, obe male mice with reconstituted Est in their adipose tissue failed to ameliorate the impairment of the structure and function of the pancreatic islets. In summary, our study uncovers a crucial adipose- and male-specific role of Est in maintaining the whole-body energy homeostasis.
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Sex-Specific Effect of Estrogen Sulfotransferase on Mouse Models of Type 2 Diabetes
Diabetes, 2012Co-Authors: Jie Gao, Xiongjie Shi, Maja Stefanovic-racic, Robert M. O'doherty, Adolfo Garcia-ocaña, Wen XieAbstract:Estrogen Sulfotransferase (EST), the enzyme responsible for the sulfonation and inactivation of Estrogens, plays an important role in Estrogen homeostasis. In this study, we showed that induction of hepatic Est is a common feature of type 2 diabetes. Loss of Est in female mice improved metabolic function in ob/ob, dexamethasone-, and high-fat diet–induced mouse models of type 2 diabetes. The metabolic benefit of Est ablation included improved body composition, increased energy expenditure and insulin sensitivity, and decreased hepatic gluconeogenesis and lipogenesis. This metabolic benefit appeared to have resulted from decreased Estrogen deprivation and increased Estrogenic activity in the liver, whereas such benefit was abolished in ovariectomized mice. Interestingly, the effect of Est was sex-specific, as Est ablation in ob/ob males exacerbated the diabetic phenotype, which was accounted for by the decreased islet β-cell mass and failure of glucose-stimulated insulin secretion in vivo. The loss of β-cell mass in ob/ob males deficient in Est was associated with increased macrophage infiltration and inflammation in white adipose tissue. Our results revealed an essential role of EST in energy metabolism and the pathogenesis of type 2 diabetes. Inhibition of EST, at least in females, may represent a novel approach to manage type 2 diabetes.
Hironobu Sasano - One of the best experts on this subject based on the ideXlab platform.
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Steroid sulfatase and Estrogen Sulfotransferase in human carcinomas.
Molecular and cellular endocrinology, 2010Co-Authors: Takashi Suzuki, Kiyoshi Ito, Yasuhiro Miki, Yasuhiro Nakamura, Hironobu SasanoAbstract:Estrogens are closely involved in the development of hormone-dependent carcinomas. Estrone is locally produced from circulating inactive estrone sulfate by steroid sulfatase (STS), while estrone is inversely inactivated into estrone sulfate by Estrogen Sulfotransferase (EST). Recent studies suggested importance of this STS pathway in various human carcinomas. Therefore, in this review, we summarized recent results of STS and EST in several Estrogen-dependent carcinomas. STS and EST expressions were detected in the breast and endometrial carcinomas, and activation of STS pathway due to increment in STS and/or decrement in EST expressions plays important role in their Estrogen-dependent growth. STS expression was also reported in the ovarian and prostate carcinomas. STS/EST status was associated with intratumoral Estrogen level in the colon carcinoma, and STS-negative/EST-positive colon carcinoma patients had longer survival. Therefore, STS pathway and Estrogen actions may play an important role in the development of these carcinomas, and further investigations are required.
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Steroid sulfatase and Estrogen Sulfotransferase in human prostate cancer
The Prostate, 2006Co-Authors: Yasuhiro Nakamura, Takashi Suzuki, Tsuyoshi Fukuda, Akihiro Ito, Mareyuki Endo, Takuya Moriya, Yoichi Arai, Hironobu SasanoAbstract:BACKGROUND Estrogen Sulfotransferase (EST) and steroid sulfatase (STS) are known to be involved in in situ Estrogen production in Estrogen dependent human cancer such as breast cancer, but unknown in prostate cancer. MATERIALS AND METHODS We first examined whether these enzymes above were expressed and actually involved in Estrogen production and metabolism in prostate cancer cell lines (LNCaP, DU-145, and PC-3). We than examined the expression of EST and STS in human prostate cancer tissues obtained from surgery (n = 52) using immunohistochemistry. RESULTS mRNAs of both enzymes were detected in all prostate cancer cell lines examined, and the synthesis of estrone (E1) and estradiol (E2) was also confirmed in these cell lines. In addition, STS immunoreactivity was detected in 44 cases (85%) and EST in 39 cases (75%), respectively. CONCLUSIONS STS and EST are expressed and may be involved in local production and metabolism of Estrogens in human prostate cancers. Prostate 66: 1005–1012, 2006. © 2006 Wiley-Liss, Inc.
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Steroid Sulfatase and Estrogen Sulfotransferase in Human Endometrial Carcinoma
Clinical Cancer Research, 2004Co-Authors: Hiroki Utsunomiya, Kiyoshi Ito, Takashi Suzuki, Takako Kitamura, Chika Kaneko, Taisuke Nakata, Hitoshi Niikura, Kunihiro Okamura, Nobuo Yaegashi, Hironobu SasanoAbstract:Purpose: Intratumoral metabolism and synthesis of Estrogens are considered to play important roles in the pathogenesis and/or development of human endometrial carcinoma. Steroid sulfatase hydrolyzes biologically inactive Estrogen sulfates to active Estrogens, whereas Estrogen Sulfotransferase sulfonates Estrogens to Estrogen sulfates. However, the status of steroid sulfatase and/or Estrogen Sulfotransferase in human endometrial carcinoma has not been examined. Experimental Design: We first examined the expression of steroid sulfatase and Estrogen Sulfotransferase in 6 normal endometrium and 76 endometrial carcinoma using immunohistochemistry to elucidate the possible involvement of steroid sulfatase and Estrogen Sulfotransferase. We then evaluated the enzymatic activity and the semiquantitative analysis of mRNA using reverse transcription-PCR in 21 endometrial carcinomas. We correlated these findings with various clinicopathological parameters including the expression of aromatase, 17β-hydroxysteroid dehydrogenase type 1 and type 2. Results: Steroid sulfatase and Estrogen Sulfotransferase immunoreactivity was detected in 65 of 76 (86%) and 22 of 76 (29%) cases, respectively. Results of immunoreactivity for steroid sulfatase and Estrogen Sulfotransferase were significantly correlated with those of enzymatic activity and semiquantitative analysis of mRNA. No significant correlations were detected among the expression of the enzymes involved in intratumoral Estrogen metabolism. There was a significant correlation between steroid sulfatase/Estrogen Sulfotransferase ratio and clinical outcomes of the patients. However, there were no significant differences between steroid sulfatase or Estrogen Sulfotransferase and Estrogen receptor, progesterone receptor, Ki67, histologic grade, or clinical outcomes of the patients. Conclusions: Results of our study demonstrated that increased steroid sulfatase and decreased Estrogen Sulfotransferase expression in human endometrial carcinomas may result in increased availability of biologically active Estrogens and may be related to Estrogen-dependent biological features of carcinoma.
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Steroid sulfatase and Estrogen Sulfotransferase in normal human tissue and breast carcinoma.
The Journal of Steroid Biochemistry and Molecular Biology, 2003Co-Authors: Takashi Suzuki, Taisuke Nakata, Yasuhiro Miki, Takuya Moriya, Yukimasa Shiotsu, Shiro Akinaga, Kengo Inoue, Takanori Ishida, Michio Kimura, Hironobu SasanoAbstract:Steroid sulfatase (STS) hydrolyzes inactive estrone sulfate (E1-S) to estrone (E1), while Estrogen Sulfotransferase (EST; SULT 1E1 or STE gene) sulfonates Estrogens to Estrogen sulfates. They are considered to play important roles in the regulation of local Estrogenic actions in various human tissues, however, their biological significance remains largely unknown. Therefore, we examined the expression of STS and EST in non-pathologic human tissues and breast carcinomas. STS expression was very weak except for the placenta, while EST expression was markedly detected in various tissues examined. In breast carcinoma tissues, STS and EST immunoreactivity was detected in carcinoma cells in 74 and 44% of cases, respectively, and was significantly associated with their mRNA levels and enzymatic activities. STS immunoreactivity was significantly correlated with the tumor size, and an increased risk of recurrence. EST immunoreactivity was inversely correlated with the tumor size or lymph node status. Moreover, EST immunoreactivity was significantly associated with a decreased risk of recurrence or improved prognosis. Our results suggest that EST is involved in protecting various peripheral tissues from excessive Estrogenic effects. In the breast carcinoma, STS and EST are suggested to play important roles in the regulation of in situ Estrogen production in the breast carcinomas.
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Estrogen Sulfotransferase and steroid sulfatase in human breast carcinoma.
Cancer research, 2003Co-Authors: Takashi Suzuki, Chika Kaneko, Taisuke Nakata, Yasuhiro Miki, Takuya Moriya, Shiro Akinaga, Takanori Ishida, Michio Kimura, Hisashi Hirakawa, Hironobu SasanoAbstract:Estrogen Sulfotransferase (EST; SULT 1E1 or STE gene) sulfonates Estrogens to inactive Estrogen sulfates, whereas steroid sulfatase (STS) hydrolyzes estrone sulfate to estrone. Both EST and STS have been suggested to play important roles in regulating the in situ production of Estrogens in human breast carcinoma tissues. However, the expression of EST has not been examined in breast carcinoma tissues, and the biological significance of EST and STS remains unknown. Therefore, in this study, we examined the expression of EST and STS in 35 specimens of human breast carcinoma tissues using immunohistochemistry, reverse transcription-PCR (RT-PCR), and enzymatic assay. EST and STS immunoreactivity was also correlated with various clinicopathological parameters, including prognosis to examine the biological significance of these enzymes in 113 breast carcinomas. EST and STS immunoreactivity was detected in carcinoma cells and significantly associated with their mRNA levels (P = 0.0027 and 0.0158, respectively), as measured by RT/real-time PCR, and enzymatic activities (P = 0.0005 and 0.0089, respectively) in 35 breast carcinomas. In breast cancer tissues examined by laser capture microdissection/RT-PCR analyses, the mRNA for EST was localized in both carcinoma and intratumoral stromal cells, whereas that of STS was detected only in carcinoma cells. Of the 113 invasive ductal carcinomas examined in this study, EST and STS immunoreactivity was detected in 50 and 84 cases (44.2 and 74.3%), respectively. In these cases, EST immunoreactivity was inversely correlated with tumor size (P = 0.003) or lymph node status (P = 0.0027). In contrast, STS immunoreactivity was significantly correlated with tumor size (P = 0.0047). Moreover, EST immunoreactivity was significantly associated with a decreased risk of recurrence or improved prognosis by both uni (P = 0.0044, and 0.0026, respectively) and multivariate (P = 0.0429 and 0.0149, respectively) analyses. STS immunoreactivity, however, was significantly associated with an increased risk of recurrence (P = 0.0118) and worsened prognosis (P = 0.0325) by univariate analysis. Results from our present study suggest that immunoreactivities for both EST and STS are associated with their mRNA level and enzymatic activity and that EST immunoreactivity is considered to be a potent prognostic factor in human breast carcinoma.