Kim Don-Kyu, Kim Yong-Hoon, Jung Yoon Seok, Kim Ki-Sun, Jeong Jae-Ho, Lee Yong-Soo, Yuk Jae-Min, Oh Byung-Chul, Choy Hyon E, Dooley Steven, Muckenthaler Martina U, Lee Chul-Ho, Choi Hueng-Sik
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, Republic of Korea.
Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
Sci Rep. 2016 Sep 30;6:34630. doi: 10.1038/srep34630.
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.
小异源二聚体伴侣蛋白（SHP）是一种调节多种代谢过程的转录共抑制因子。在此，我们表明SHP作为铁稳态的内在负调节因子发挥作用。与野生型小鼠相比，维持高铁饮食的SHP缺陷型小鼠血清铁调素水平升高，铁输出蛋白铁转运蛋白的表达降低以及铁蓄积。相反，SHP或AMP激活的蛋白激酶（AMPK，一种诱导SHP表达的代谢传感器）的过表达抑制了BMP6诱导的铁调素表达。此外，通过消除SHP表达，AMPK激活剂二甲双胍和AICAR对BMP6介导的铁调素基因表达的抑制作用显著减弱。有趣的是，SHP与SMAD1发生物理相互作用，并通过抑制SMAD1和SMAD4复合物的形成来抑制BMP6介导的SMAD复合物募集到铁调素基因启动子。最后，SHP的过表达和对BMP6刺激的小鼠进行二甲双胍治疗可使铁调素表达和血清铁基本恢复到基线水平。这些结果揭示了SHP在铁稳态转录控制中以前未被认识的作用。
