Estrogen sulfotransferase (SULT1E1) metabolically inactivates estrogen and SULT1E1 expression is tightly regulated by multiple nuclear receptors. Human fetal, but not adult, livers express appreciable amounts of SULT1E1 protein, which is mimicked in human hepatoma-derived HepG2 cells cultured in high glucose (450 mg/dl) medium. Here, we have investigated this glucose signal that leads to phosphorylation of nuclear receptor RORα (NR1F1) at Ser100 and the transcription mechanism by which phosphorylated RORα transduces this signal to nuclear receptor HNF4α, activating the SULT1E1 promoter. The promoter is repressed by non-phosphorylated RORα which binds a distal enhancer (−943/−922 bp) and interacts with and represses HNF4α-mediated transcription. In response to high glucose, RORα becomes phosphorylated at Ser100 and reverses its repression of HNF4α promoter activation. Moreover, the casein kinase CK1α, which is identified in an enhancer-bound nuclear protein complex, phosphorylates Ser100 in in vitro kinase assays. During these dynamic processes, both RORα and HNF4α remain on the enhancer. Thus, RORα utilizes phosphorylation to integrate HNF4α and transduces the glucose signal to regulate the SULT1E1 gene in HepG2 cells and this phosphorylation-mediated mechanism may also regulate SULT1E1 expressions in the human liver.

中文翻译：

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酪蛋白激酶1α的RORα磷酸化作为葡萄糖信号调节人肝细胞中的雌激素硫酸化。

雌激素磺基转移酶（SULT1E1）在代谢上使雌激素失活，并且SULT1E1的表达受到多种核受体的严格调控。人类胎儿而非成人肝脏表达大量SULT1E1蛋白，该蛋白在高葡萄糖（450 mg / dl）培养基中培养的人肝癌衍生的HepG2细胞中被模仿。在这里，我们研究了这种葡萄糖信号，该信号导致Ser100核受体RORα（NR1F1）磷酸化，磷酸化RORα将该信号转导至核受体HNF4α从而激活SULT1E1启动子的转录机制。该启动子被非磷酸化的RORα抑制，该RORα结合远端增强子（-943 / -922 bp），并与HNF4α介导的转录相互作用并抑制该转录。为了应对高血糖，RORα在Ser100处被磷酸化，并逆转其对HNF4α启动子激活的抑制。此外，在增强子结合核蛋白复合物中鉴定出的酪蛋白激酶CK1α在体外激酶测定中可使Ser100磷酸化。在这些动态过程中，RORα和HNF4α均保留在增强子上。因此，RORα利用磷酸化整合HNF4α并转导葡萄糖信号以调节HepG2细胞中的SULT1E1基因，并且这种磷酸化介导的机制也可能调节人肝中SULT1E1的表达。