Abstract
Small heterodimer partner (SHP) is a transcriptional corepressor regulating diverse metabolic processes. Here, we show that SHP acts as an intrinsic negative regulator of iron homeostasis. SHP-deficient mice maintained on a high-iron diet showed increased serum hepcidin levels, decreased expression of the iron exporter ferroportin as well as iron accumulation compared to WT mice. Conversely, overexpression of either SHP or AMP-activated protein kinase (AMPK), a metabolic sensor inducing SHP expression, suppressed BMP6-induced hepcidin expression. In addition, an inhibitory effect of AMPK activators metformin and AICAR on BMP6-mediated hepcidin gene expression was significantly attenuated by ablation of SHP expression. Interestingly, SHP physically interacted with SMAD1 and suppressed BMP6-mediated recruitment of the SMAD complex to the hepcidin gene promoter by inhibiting the formation of SMAD1 and SMAD4 complex. Finally, overexpression of SHP and metformin treatment of BMP6 stimulated mice substantially restored hepcidin expression and serum iron to baseline levels. These results reveal a previously unrecognized role for SHP in the transcriptional control of iron homeostasis.
Highlights
The hepatic peptide hormone hepcidin coordinates body iron homeostasis that is maintained by the tight regulation of dietary iron absorption and release of iron from macrophages and hepatocytes[1]
These results suggest that BMP6 and Small heterodimer partner (SHP) are involved in iron-mediated regulation of hepcidin expression in mouse liver
SHP was reported to act as a transcriptional corepressor of CCAAT/ enhancer-binding protein alpha and estrogen-related receptor gamma, both involved in the transcriptional regulation of hepcidin expression[19,20]
Summary
The hepatic peptide hormone hepcidin coordinates body iron homeostasis that is maintained by the tight regulation of dietary iron absorption and release of iron from macrophages and hepatocytes[1]. The hepcidin response to inflammation mediated by stimuli, such as interleukin-6 (IL-6), requires activation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling in hepatocytes[3,4]. The iron-response of hepcidin is further regulated by bone morphogenetic protein (BMP)-SMAD signaling[5,6,7]. Small heterodimer partner (SHP; NR0B2) is an atypical orphan member of the nuclear receptor superfamily that lacks the conventional DNA binding domain[9]. We demonstrated that SHP gene expression is strongly induced by AMPK activators such as metformin, sodium arsenite, hepatocyte growth factor, and macrophage-stimulating factor, leading to inhibition of hepatic gluconeogenesis[13,14,15]. We describe SHP as transcriptional corepressor of BMP6-mediated hepcidin expression that is triggered by an iron signal
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