Orphan nuclear receptor SHP regulates iron metabolism through inhibition of BMP6-mediated hepcidin expression.
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.
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.
Don-Kyu
DK
Kim
Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
Yong-Hoon
YH
Kim
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.
Yoon Seok
YS
Jung
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.
Ki-Sun
KS
Kim
Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Jae-Ho
JH
Jeong
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.
Yong-Soo
YS
Lee
Department of Medical Science and Infection Biology, Chungnam National University School of Medicine, Daegeon, Republic of Korea.
Jae-Min
JM
Yuk
Lee Gil Ya Cancer and Diabetes Institute, Gachon University Graduate School of Medicine, Incheon, Republic of Korea.
Byung-Chul
BC
Oh
Department of Microbiology, Chonnam National University Medical School, Gwangju, Republic of Korea.
Hyon E
HE
Choy
Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Steven
S
Dooley
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, University of Heidelberg, Heidelberg, Germany.
Martina U
MU
Muckenthaler
Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology (UST), Yuseong-gu, Daejeon, Republic of Korea.
Chul-Ho
CH
Lee
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.
Hueng-Sik
HS
Choi
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