Farnesoid X receptor represses human sulfotransferase 1A3 expression through direct binding to the promoter,Chemical Biology & Drug Design

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Farnesoid X receptor represses human sulfotransferase 1A3 expression through direct binding to the promoter
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2023-07-24 , DOI: 10.1111/cbdd.14312
Yuanyuan Dou ₁ , Shuhua Pei ₁ , Yingying Li ₁ , Mengqing Wang ₁ , Zhuangzhuang Liu ₁ , Jiqin Li ₁ , Jinlan Cao ₁ , Jia Qin ₁ , Mingzhu Zhang ₁ , Lili Hou ₁ , Hua Sun _{1,

2,

3}

Affiliation

Human sulfotransferases 1A3 (SULT1A3) has received particular interest, due to their functions of catalyzing the sulfonation of numerous phenolic substrates, including bioactive endogenous molecules and therapeutic agents. However, the regulation of SULT1A3 expression and the underlying mechanism remain unclear. Here, we aimed to investigate the regulation effects of bile acid-activated farnesoid X receptor (FXR) on SULT1A3 expression, and to shed light on the mechanism thereof. Our results demonstrated that FXR agonists (CDCA and GW4064) significantly inhibit the expression of SULT1A3 at mRNA and protein levels. In addition, overexpression of FXR led to decrease in SULT1A3 expression and knockdown of FXR significantly induced the expression of SULT1A3 in protein and mRNA levels, confirming that FXR expression manifestly showed negative regulatory effect on basal SULT1A3 expression. Furthermore, a combination of luciferase reporter gene and CHIP assays showed that FXR repressed SULT1A3 transcription through direct binding to the region at base pair positions −664 to −654. In conclusion, this study for the first time confirmed FXR was a negative transcriptional regulator of human SULT1A3 enzyme.

中文翻译：

Farnesoid X 受体通过直接结合启动子抑制人磺基转移酶 1A3 表达

人磺基转移酶 1A3 (SULT1A3) 由于其催化多种酚类底物（包括生物活性内源性分子和治疗剂）磺化的功能而受到特别关注。然而，SULT1A3表达的调控及其潜在机制仍不清楚。在此，我们的目的是研究胆汁酸激活的法尼醇X受体（FXR）对SULT1A3表达的调节作用，并阐明其机制。我们的结果表明，FXR 激动剂（CDCA 和 GW4064）在 mRNA 和蛋白质水平上显着抑制 SULT1A3 的表达。此外，FXR的过表达导致SULT1A3表达减少，FXR的敲除显着诱导SULT1A3蛋白和mRNA水平的表达，证实FXR表达对基础SULT1A3表达明显表现出负调节作用。此外，荧光素酶报告基因和 CHIP 测定的组合表明，FXR 通过直接结合到碱基对位置 -664 至 -654 的区域来抑制 SULT1A3 转录。总之，本研究首次证实FXR是人SULT1A3酶的负转录调节因子。

更新日期：2023-07-24

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