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Literature summary for 2.8.2.4 extracted from
- Sex-dependent role of estrogen sulfotransferase and steroid sulfatase in metabolic homeostasis (2017), Adv. Exp. Med. Biol., 1043, 455-469 .
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| additional information | elevated EST expression in white adipose tissue (WAT) in obese men and women is significantly associated with the expression of tumor necrosis factor alpha (TNF-alpha) and suppressor of cytokine signaling-3 (SOCS3), a downstream target of TNF-alpha and a marker of inflammation | Homo sapiens |
| additional information | the mRNA and protein expression of EST is highly induced in the livers of obese and diabetogenic leptin receptor deficient C57BL/KsJ-db/db mice. The db/db genotype does not change the constitutive expression of the enzyme in the testis. The leptin-deficient ob/ob mice as well as wild-type mice fed with Western style high-fat diet also show increased expression of EST specifically in the liver. The expression of EST can also be stimulated in the liver by dexamethasone through the activation of the glucocorticoid receptor (GR). The activation of GR can lead to hyperglycemia in genetically obese viable yellow (Avy) female mice due to an aberrant shift in hepatic androgen/ estrogen balance. Overexpression of EST in 3T3-L1 cells or transgenic expression of EST in the WAT of female mice results in decreased differentiation of primary adipocytes and smaller adipocyte size, suggesting that conditional EST expression/activity in WAT has a profound effect on female adiposity. Only tissue-specific or local changes in insulin sensitivity were shown in the female murine model of WAT-EST overexpression. Transgenic expression of EST in female WAT does not significantly change the mRNA expression levels of proinflammatory genes such as MCP1 and IL-beta | Mus musculus |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| cytosol | - |
Homo sapiens | 5829 | - |
| cytosol | - |
Mus musculus | 5829 | - |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| 3'-phosphoadenylyl sulfate + 17beta-estradiol | Homo sapiens | - |
adenosine 3',5'-bisphosphate + 17beta-estradiol 3-sulfate | - |
? |  |
| 3'-phosphoadenylyl sulfate + 17beta-estradiol | Mus musculus | - |
adenosine 3',5'-bisphosphate + 17beta-estradiol 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + 17beta-estradiol | Mus musculus C57BL/6J | - |
adenosine 3',5'-bisphosphate + 17beta-estradiol 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + diethylstilbestrol | Homo sapiens | - |
adenosine 3',5'-bisphosphate + diethylstilbestrol sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + diethylstilbestrol | Mus musculus | - |
adenosine 3',5'-bisphosphate + diethylstilbestrol sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + diethylstilbestrol | Mus musculus C57BL/6J | - |
adenosine 3',5'-bisphosphate + diethylstilbestrol sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + estrone | Homo sapiens | - |
adenosine 3',5'-bisphosphate + estrone 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + estrone | Mus musculus | - |
adenosine 3',5'-bisphosphate + estrone 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + estrone | Mus musculus C57BL/6J | - |
adenosine 3',5'-bisphosphate + estrone 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + tamoxifen | Homo sapiens | - |
adenosine 3',5'-bisphosphate + tamoxifen sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + tamoxifen | Mus musculus | - |
adenosine 3',5'-bisphosphate + tamoxifen sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + tamoxifen | Mus musculus C57BL/6J | - |
adenosine 3',5'-bisphosphate + tamoxifen sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + testosterone | Homo sapiens | - |
adenosine 3',5'-bisphosphate + testosterone sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + testosterone | Mus musculus | - |
adenosine 3',5'-bisphosphate + testosterone sulfate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P49888 | - |
- |
| Mus musculus | P49891 | - |
- |
| Mus musculus C57BL/6J | P49891 | - |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| adipocyte | EST is predominantly expressed in stromal vascular cells (pre-adipocytes). Consistent with the pre-adipocyte pattern of expression, the expression of EST is dramatically reduced in differentiated 3T3-L1 cells or mature primary adipocytes | Mus musculus | - |
| adipose tissue | EST expression is detectable in the subcutaneous adipose tissue in both obese women and men. The expression of EST in the abdominal subcutaneous fat of obese and nonobese female human subjects and in primary adipose-derived stem cells (ASCs) isolated from female subjects is low, but the expression of EST increases with the onset of differentiation. EST is detectable in the subcutaneous adipose tissue in both obese women and men, especially in the abdominal area | Homo sapiens | - |
| adipose-derived stromal cell | pre-adipocytes, predominantly | Mus musculus | - |
| adrenal cortex | - |
Homo sapiens | - |
| brain | - |
Homo sapiens | - |
| epididymis | high level in males. Castration of male mice abolishes EST expression in the epididymal fat, whereas testosterone supplementation restores it, suggesting that EST expression in male WAT is testosterone-dependent | Mus musculus | - |
| epithelial cell | - |
Homo sapiens | - |
| fat pad | high level in males. Castration of male mice abolishes EST expression in the epididymal fat, whereas testosterone supplementation restores it, suggesting that EST expression in male WAT is testosterone-dependent | Mus musculus | - |
| gastrointestinal tract | epithelial cells | Homo sapiens | - |
| hepatocyte | - |
Homo sapiens | - |
| hepatoma cell | - |
Homo sapiens | - |
| Huh-7 cell | - |
Homo sapiens | - |
| kidney | - |
Homo sapiens | - |
| liver | - |
Homo sapiens | - |
| liver | low level under normal diet | Mus musculus | - |
| additional information | in mice, the expression of EST shows sex specificity. Male, but not female, mice express a high basal level of EST in the white adipose tissue (WAT). The expression of EST in the male epididymal fat pad is particularly highly. The expression of EST is also detected at a lower level in several other white adipose depots, but not in the brown adipose tissue | Mus musculus | - |
| additional information | STS is upregulated in patients with chronic inflammatory liver diseases. Tissue distribution and the transcriptional regulation of EST and STS exhibit obvious sex and species specificity | Homo sapiens | - |
| primary cell | - |
Homo sapiens | - |
| white adipose tissue | - |
Homo sapiens | - |
| white adipose tissue | WAT, high level in females. EST expression in male WAT is testosterone-dependent. Although the basal expression of Est in the female mouse WAT is low, it can be induced in the parametrial fat by testosterone treatment. The induction of EST expression by testosterone in female mice is WAT specific, because testosterone treatment fails to induce the expression of EST in the liver | Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| 3'-phosphoadenylyl sulfate + 17beta-estradiol | - |
Homo sapiens | adenosine 3',5'-bisphosphate + 17beta-estradiol 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + 17beta-estradiol | - |
Mus musculus | adenosine 3',5'-bisphosphate + 17beta-estradiol 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + 17beta-estradiol | - |
Mus musculus C57BL/6J | adenosine 3',5'-bisphosphate + 17beta-estradiol 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + diethylstilbestrol | - |
Homo sapiens | adenosine 3',5'-bisphosphate + diethylstilbestrol sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + diethylstilbestrol | - |
Mus musculus | adenosine 3',5'-bisphosphate + diethylstilbestrol sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + diethylstilbestrol | - |
Mus musculus C57BL/6J | adenosine 3',5'-bisphosphate + diethylstilbestrol sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + estrone | - |
Homo sapiens | adenosine 3',5'-bisphosphate + estrone 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + estrone | - |
Mus musculus | adenosine 3',5'-bisphosphate + estrone 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + estrone | - |
Mus musculus C57BL/6J | adenosine 3',5'-bisphosphate + estrone 3-sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + tamoxifen | - |
Homo sapiens | adenosine 3',5'-bisphosphate + tamoxifen sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + tamoxifen | - |
Mus musculus | adenosine 3',5'-bisphosphate + tamoxifen sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + tamoxifen | - |
Mus musculus C57BL/6J | adenosine 3',5'-bisphosphate + tamoxifen sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + testosterone | - |
Homo sapiens | adenosine 3',5'-bisphosphate + testosterone sulfate | - |
? | |
| 3'-phosphoadenylyl sulfate + testosterone | - |
Mus musculus | adenosine 3',5'-bisphosphate + testosterone sulfate | - |
? | |
| additional information | EST has a particularly high affinity for estrogens as substrates including estradiol (17beta-estradiol), estrone, and a variety of synthetic estrogens, like diethylstilbestrol and tamoxifen. EST also exhibits a low affinity for thyroid hormones, testosterones, or glucocorticoids | Homo sapiens | ? | - |
- |
|
| additional information | EST has a particularly high affinity for estrogens as substrates including estradiol (17beta-estradiol), estrone, and a variety of synthetic estrogens, like diethylstilbestrol and tamoxifen. EST also exhibits a low affinity for thyroid hormones, testosterones, or glucocorticoids | Mus musculus | ? | - |
- |
|
| additional information | EST has a particularly high affinity for estrogens as substrates including estradiol (17beta-estradiol), estrone, and a variety of synthetic estrogens, like diethylstilbestrol and tamoxifen. EST also exhibits a low affinity for thyroid hormones, testosterones, or glucocorticoids | Mus musculus C57BL/6J | ? | - |
- |
|
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| EST | - |
Homo sapiens |
| EST | - |
Mus musculus |
| estrogen sulfotransferase | - |
Homo sapiens |
| estrogen sulfotransferase | - |
Mus musculus |
| SULT1E1 | - |
Homo sapiens |
| SULT1E1 | - |
Mus musculus |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | a confirmed repressor of EST gene in human primary hepatocytes and hepatocellular carcinoma Huh7 cells is pregnane X receptor (PXR), when the PXR is activated by rifampicin. Aryl hydrocarbon receptor (AhR) activation has also been shown to suppress EST expression | down |
| Homo sapiens | hepatic EST is also positively regulated by the liver X receptor (LXR). The induction of EST in acute inflammation in sepsis model is nuclear factor kappa-B (NF-kappaB) dependent, and EST is an NF-kappaB target gene. Inflammation and oxidative stress induce the activation of nuclear factor 2 (Nrf2), followed by the induction of EST who is a direct transcriptional target of Nrf2 | up |
| Mus musculus | the mRNA and protein expression of EST is highly induced in the livers of obese and diabetogenic leptin receptor deficient C57BL/KsJ-db/db mice. The leptin-deficient ob/ob mice as well as wild-type mice fed with Western style high-fat diet also show increased expression of EST specifically in the liver. The expression of EST can also be stimulated in the liver by dexamethasone through the activation of the glucocorticoid receptor (GR). Although the basal expression of Est in the female mouse WAT is low, it can be induced in the parametrial fat by testosterone treatment. The induction of EST expression by testosterone in female mice is WAT specific, because testosterone treatment fails to induce the expression of EST in the liver. The xenobiotic nuclear receptor, constitutive androstane receptor (CAR), induces the expression of EST in the mouse liver in response to diallyl sulfide (DAS) treatment. Environmental pollutants such as dioxin, polychlorinated biphenyl 153, or bisphenol A have also been reported to induce the hepatic expression of EST in a sex-specific manner. Another inducer of EST expression is hypoxia and oxidative stress as shown in the mouse model of liver ischemia and reperfusion (I/R) injury. Inflammation and oxidative stress induce the activation of nuclear factor 2 (Nrf2), followed by the induction of EST who is a direct transcriptional target of Nrf2 | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| evolution | the estrogen sulfotransferase (EST or SULT1E1) is a member of the sulfotransferase family. It shares high amino acid homology with other sulfotransferase isoforms. But EST is believed to have unique functions due to its distinct substrates and specific tissue distribution and sex-regulated expression. The effect of EST on adipogenesis seems to be species specific. The anti-adipogenic activity of EST in mice is opposite to the pro-adipogenic effect of the same enzyme in human adipocytes | Homo sapiens |
| evolution | the estrogen sulfotransferase (EST or SULT1E1) is a member of the sulfotransferase family. It shares high amino acid homology with other sulfotransferase isoforms. But EST is believed to have unique functions due to its distinct substrates and specific tissue distribution and sex-regulated expression. The effect of EST on adipogenesis seems to be species specific. The anti-adipogenic activity of EST in mice is opposite to the pro-adipogenic effect of the same enzyme in human adipocytes | Mus musculus |
| malfunction | EST ablation produces completely opposite metabolic phenotype in female and male obese mice. Male Est-/- mice develop age-dependent Leydig cell hypertrophy/hyperplasia and impaired steroidogenesis, have reduced total and forward sperm motility, and produce smaller litters compared with age-matched wild-type males. In female mice, ablation of the mouse Sult1e1 gene causes placental thrombosis and spontaneous fetal loss, which is associated with elevated free estrogen levels in the circulation and the amniotic fluid. The expression of EST can also be stimulated in the liver by dexamethasone through the activation of the glucocorticoid receptor (GR). The activation of GR can lead to hyperglycemia in genetically obese viable yellow (Avy) female mice due to an aberrant shift in hepatic androgen/ estrogen balance. Castration of male mice abolishes EST expression in the epididymal fat, whereas testosterone supplementation restores it. Although EST expression can be induced in the parametrial fat of female mice, whole body ablation of EST does not cause any differences in fat indices (fat weight normalized to body weight) between female WT and EST-/- mice. EST-/- male mice have their epididymal and inguinal fat indices significantly higher than those of the wild-type mice. Adipocyte size in EST-/- male mice is markedly larger than that of wild-type mice, but under chow diet, these changes are not accompanied by obvious metabolic abnormalities. EST loss in obese males worsens metabolic phenotype. Female obe mice exhibit completely opposite metabolic phenotypes. Whole body loss of EST expression in the ob/ob background decreases hepatic gluconeogenesis and lipogenesis, improves body composition and insulin sensitivity, and increases energy expenditure. Ablation of EST in female ob/ob mice does not affect WAT inflammation | Mus musculus |
| metabolism | 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, EC 3.1.6.2) 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. Sex-dependent role of estrogen sulfotransferase and steroid sulfatase in metabolic homeostasis | Mus musculus |
| metabolism | 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 (STSEC 3.1.6.2) 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. Sex-dependent role of estrogen sulfotransferase and steroid sulfatase in metabolic homeostasis | Homo sapiens |
| additional information | adipogenesis is differentially regulated by EST in murine and human adipocytes | Homo sapiens |
| additional information | adipogenesis is differentially regulated by EST in murine and human adipocytes | Mus musculus |
| physiological function | estrogen sulfotransferase (EST) mediates sulfation and deactivation of estrogens. Consistent with the function of EST in estrogen sulfation and deactivation, EST plays an important role in protecting the reproductive tissue in both sexes. EST plays a role in inhibiting the estrogen-dependent growth of breast cancer cells both in vitro and in vivo through its activity in deactivating estrogens. Overexpression of EST in 3T3-L1 cells or transgenic expression of EST in the white adipose tissue (WAT) of female mice results in decreased differentiation of primary adipocytes and smaller adipocyte size, suggesting that conditional EST expression/activity in WAT has a profound effect on female adiposity, inhibitory effect of EST on adipogenesis probably resulting from the activation of ERK1/2 MAPK and inhibition of insulin signaling, which explains a blunted glucose uptake in parametrial adipose tissue during the hyperinsulinemic-euglycemic clamp in EST transgenic female mice. Although EST expression can be induced in the parametrial fat of female mice, whole body ablation of EST does not cause any differences in fat indices (fat weight normalized to body weight) between female wild-type and EST-/- mice. The obese males that have higher fasting glucose level and worse glucose tolerance performance also show impaired glucose-stimulated insulin secretion. Transgenic expression of EST in female WAT does not significantly change the mRNA expression levels of proinflammatory genes such as MCP1 and IL-beta | Mus musculus |
| physiological function | estrogen sulfotransferase (EST) mediates sulfation and deactivation of estrogens. Consistent with the function of EST in estrogen sulfation and deactivation, EST plays an important role in protecting the reproductive tissue in both sexes. EST plays a role in inhibiting the estrogen-dependent growth of breast cancer cells both in vitro and in vivo through its activity in deactivating estrogens. The pro-adipogenic effect resulting from EST overexpression in primary adipose-derived stem cells (ASCs) can be mimicked by using an estrogen receptor (ER) antagonist or ER knockdown, suggesting that EST promotes adipogenesis by deactivating estrogens. Although the expression of EST can be positively associated with general adiposity or BMI scores, it does not correlate with the circulating levels of estradiol or testosterone in both men and women. EST through controlling the local availability of the estrogens has a profound effect on adipocyte metabolism and growth. Elevated EST expression in white adipose tissue (WAT) in obese men and women is significantly associated with the expression of tumor necrosis factor alpha (TNF-alpha) and suppressor of cytokine signaling-3 (SOCS3), a downstream target of TNF-alpha and a marker of inflammation. Potential inflammatory regulation of the enzyme, at least in human adipose tissues | Homo sapiens |
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