Dexamethasone-induced hyperglycemia in obese Avy/a (viable yellow) female mice entails preferential induction of a hepatic estrogen sulfotransferase

Although primarily regarded as a sex steroid, estrogen plays an important role in many other physiological processes including adipose development and disposition. Estrogen sulfotransferase (EST) regulates estrogen activity by catalyzing the sulfoconjugation and inactivation of estrogens. In the present study, we report the gender-specific expression of EST in adipose tissues of the mouse and describe contrasting mechanisms of EST regulation in the fat and liver. EST is expressed in the white adipose tissues of the male but not female mouse. Within the various fat depots of male mice, it is most abundantly expressed in the epididymal fat pad, with variable levels in other white fats and no expression in the brown fat. Fractionation of epididymal fat cells showed EST to be predominantly associated with stromal vascular cells (preadipocyte). EST expression in male mouse adipose tissues is dependent on testosterone as castration ablated, and administration of exogenous testosterone restored, EST expression. Furthermore, testosterone treatment induced abnormal EST expression in the parametrial fat of female mice. EST induction by testosterone in female mice is tissue specific because testosterone treatment had no effect on liver EST expression. Conversely, the liver X receptor agonist TO-901317 induced EST expression in female mouse liver but not in their adipose tissues. Finally, we demonstrate that male EST knockout mice developed increased epididymal fat accumulation with enlarged adipocyte size. We conclude that EST is expressed in adipose tissues in a sexually dimorphic manner, is regulated by testosterone, and plays a physiological role in regulating adipose tissue accumulation in male mice.

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Estrogen sulfotransferase regulates body fat and glucose homeostasis in female mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00707.2009 ◽

2010 ◽

Vol 299 (4) ◽

pp. E657-E664 ◽

Cited By ~ 23

Author(s):

Victor K. Khor ◽

Ravindra Dhir ◽

Xiaoyan Yin ◽

Rexford S. Ahima ◽

Wen-Chao Song

Keyword(s):

Adipose Tissue ◽

Insulin Sensitivity ◽

Transgenic Mice ◽

Glucose Homeostasis ◽

Fatty Acid Synthase ◽

Hormone Sensitive Lipase ◽

Estrogen Sulfotransferase ◽

Female Mice ◽

Brown Adipose ◽

Adipose Mass

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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Hepatic Estrogen Sulfotransferase Distantly Sensitizes Mice to Hemorrhagic Shock-Induced Acute Lung Injury

Endocrinology ◽

10.1210/endocr/bqz031 ◽

2019 ◽

Vol 161 (1) ◽

Cited By ~ 1

Author(s):

Yang Xie ◽

Anne Caroline S Barbosa ◽

Meishu Xu ◽

Patrick J Oberly ◽

Songrong Ren ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Hemorrhagic Shock ◽

Pulmonary Inflammation ◽

Neutrophil Infiltration ◽

Estrogen Sulfotransferase ◽

Tissue Specific ◽

Genetic Ablation ◽

Female Mice ◽

Pharmacological Inhibition

Abstract 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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Inhibition of Estrogen Sulfotransferase (SULT1E1/EST) Ameliorates Ischemic Acute Kidney Injury in Mice

Journal of the American Society of Nephrology ◽

10.1681/asn.2019080767 ◽

2020 ◽

Vol 31 (7) ◽

pp. 1496-1508

Author(s):

Anne C. Silva Barbosa ◽

Dong Zhou ◽

Yang Xie ◽

You-Jin Choi ◽

Hung-Chun Tung ◽

...

Keyword(s):

Knockout Mice ◽

Ischemia Reperfusion ◽

Kidney Injury ◽

Renal Ischemia ◽

Male Mice ◽

Wild Type ◽

Estrogen Sulfotransferase ◽

Female Mice ◽

Pharmacologic Inhibition

BackgroundStudies have suggested that estrogens may protect mice from AKI. Estrogen sulfotransferase (SULT1E1, or EST) plays an important role in estrogen homeostasis by sulfonating and deactivating estrogens, but studies on the role of SULT1E1 in AKI are lacking.MethodsWe used the renal ischemia-reperfusion model to investigate the role of SULT1E1 in AKI. We subjected wild-type mice, Sult1e1 knockout mice, and Sult1e1 knockout mice with liver-specific reconstitution of SULT1E1 expression to bilateral renal ischemia-reperfusion or sham surgery, either in the absence or presence of gonadectomy. We assessed relevant biochemical, histologic, and gene expression markers of kidney injury. We also used wild-type mice treated with the SULT1E1 inhibitor triclosan to determine the effect of pharmacologic inhibition of SULT1E1 on AKI.ResultsAKI induced the expression of Sult1e1 in a tissue-specific and sex-specific manner. It induced expression of Sult1e1 in the liver in both male and female mice, but Sult1e1 induction in the kidney occurred only in male mice. Genetic knockout or pharmacologic inhibition of Sult1e1 protected mice of both sexes from AKI, independent of the presence of sex hormones. Instead, a gene profiling analysis indicated that the renoprotective effect was associated with increased vitamin D receptor signaling. Liver-specific transgenic reconstitution of SULT1E1 in Sult1e1 knockout mice abolished the protection in male mice but not in female mice, indicating that Sult1e1’s effect on AKI was also tissue-specific and sex-specific.ConclusionsSULT1E1 appears to have a novel function in the pathogenesis of AKI. Our findings suggest that inhibitors of SULT1E1 might have therapeutic utility in the clinical management of AKI.

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