Nuclear receptor CAR-ER\u03b1 signaling regulates the estrogen sulfotransferase gene in the liver

MyeongJin Yi,Shingo Arakawa,Muluneh Fashe,Masahiko Negishi,Tatsuya Sueyoshi,Rick Moore

doi:10.1038/s41598-020-61767-9

Abstract

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.

Highlights

Estrogen sulfotransferase (SULT1E1) inactivates estrogen and regulates its metabolic homeostats
Ablation of the Sult[1] gene affected on diabetic phenotypes in mice, demonstrating that SULT1E1 plays a role in regulating hepatic metabolic syndrome[12]. It was examined whether estrogen receptor α (ERα) regulates the Sult1e1 gene and whether CAR plays a role in this regulation in diabetic livers
One-way ANOVA was used as a statistical analysis for data set of ERα S216A KI, and Kruskal-Wallis test was used to analyze the data set of ERα KO

Summary

Introduction

Estrogen sulfotransferase (SULT1E1) inactivates estrogen and regulates its metabolic homeostats. 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. 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. When ERα, CAR or SULT1E1 was ablated in mice, their livers developed similar metabolic disorders and affected on diabetic phenotypes[11,20,21], suggesting that the Sult1e1 gene may be a common target of CAR and ERα, these two nuclear receptors may directly interact to regulate the gene. It is possible that CAR interacts with ERα through its phosphorylation at Ser[216] to activate the Sult1e1 gene may undergo the same regulation

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