Regulation of Hepatic Six Transmembrane Epithelial Antigen of Prostate 4 (STEAP4) Expression by STAT3 and CCAAT/Enhancer-binding Protein α

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.