Regulation of Hepatic Six Transmembrane Epithelial Antigen of Prostate 4 (STEAP4) Expression by STAT3 and CCAAT/Enhancer-binding Protein α
Regulation of Hepatic Six Transmembrane Epithelial Antigen of Prostate 4 (STEAP4) Expression by STAT3 and CCAAT/Enhancer-binding Protein α
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DOI：
10.1074/jbc.m109.066936
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发表时间：
2010-05-28
影响因子：
4.8
通讯作者：
Hollenberg, Anthony N.
中科院分区：
文献类型：
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作者：
Ramadoss, Preeti;Chiappini, Franck;Hollenberg, Anthony N.
STEAP 4是一种质膜金属还原酶，参与铁和铜的转运。最近，STEAP 4通过作用于白色脂肪组织以控制炎性细胞因子如白细胞介素6的产生而参与促进胰岛素敏感性。事实上，小鼠中STEAP 4表达的丧失导致内脏白色脂肪组织中炎性细胞因子的产生增加和全身胰岛素抵抗。在这项研究中，我们证明小鼠肝脏中STEAP 4的产生水平显着，并且STEAP 4的转录由白细胞介素6诱导。我们进一步证明了steap 4基因是小鼠肝脏中磷酸化STAT 3的直接靶点。此外，肝脏STEAP 4表达受进食和禁食调节，肥胖导致肝脏中STEAP 4表达的诱导。有趣的是，STEAP 4在进食和禁食以及肥胖状态下的调节似乎需要转录因子CCAAT/增强子结合蛋白α，其可能与STAT 3协同作用，因为它们都与体内近端STEAP 4启动子结合。综上所述，这些数据表明肝脏STEAP 4的转录调控可能在营养和炎症应激反应中起关键作用，并有助于STEAP 4在体内的保护作用。
STEAP4 is a plasma membrane metalloreductase involved in the transport of iron and copper. Recently, STEAP4 was implicated in promoting insulin sensitivity by acting in white adipose tissue to control the production of inflammatory cytokines such as interleukin 6. Indeed, the loss of STEAP4 expression in mice leads to increased production of inflammatory cytokines in visceral white adipose tissue and systemic insulin resistance. In this study, we demonstrate that in mouse liver STEAP4 is produced at significant levels and that steap4 transcription is induced by interleukin 6. We further demonstrate that the steap4 gene is a direct target of phosphorylated STAT3 in mouse liver. In addition, hepatic STEAP4 expression is regulated by feeding and fasting, and obesity leads to the induction of STEAP4 expression in the liver. Interestingly, the regulation of STEAP4 in both feeding and fasting and the obese state appears to require the transcription factor CCAAT/enhancer-binding protein alpha that may act in concert with STAT3 as they both bind to the proximal steap4 promoter in vivo. Taken together, these data suggest the transcriptional regulation of hepatic STEAP4 may play a critical role in the response to nutritional and inflammatory stress and contributes to the protective effect of STEAP4 in vivo.