TY - JOUR
T1 - Lipogenic SREBP-1a/c transcription factors activate expression of the iron regulator hepcidin, revealing cross-talk between lipid and iron metabolisms
AU - Xiaoli, Alus M.
AU - Song, Ziyi
AU - Yang, Fajun
N1 - Publisher Copyright:
© 2019 Xiaoli et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2019/8/23
Y1 - 2019/8/23
N2 - The sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors best known for stimulating the expression of genes encoding key lipogenic enzymes. However, SREBP functions beyond lipid metabolism are less understood. Here, we show that hepcidin antimicrobial peptide (Hamp), encoding the hormone hepcidin essential for iron homeostasis and regulated by dietary iron and inflammation, is a target gene of the two SREBP isoforms SREBP-1a/c.Wefound that in tissue culture, mature, active, and nuclear forms of the SREBP-1a/c proteins induce endogenous Hamp gene expression and increase the Hamp promoter activity primarily via three regulatory sequences, including an E-box. Moreover, ChIP experiments revealed that SREBP-1a binds to the Hamp gene promoter. Overexpression of nuclear SREBP-1a under the control of the phosphoenolpyruvate carboxylase-1 (Pck1) promoter in mice increased hepatic Hamp mRNA and blood hepcidin levels, and as expected, caused fatty liver. Consistent with the known effects of Hamp up-regulation, SREBP-1a-overexpressing mice displayed signs of dysregulation in iron metabolism, including reduced serum iron and increased hepatic and splenic iron storage. Conversely, liver-specific depletion of the nuclear forms of SREBPs, as in SREBP cleavage- activating protein knockout mice, impaired lipopolysaccharide- induced up-regulation of hepatic Hamp. Together, these results indicate that the SREBP-1a/c transcription regulators activate hepcidin expression and thereby contribute to the control of mammalian iron metabolism.
AB - The sterol regulatory element-binding proteins (SREBPs) are a family of transcription factors best known for stimulating the expression of genes encoding key lipogenic enzymes. However, SREBP functions beyond lipid metabolism are less understood. Here, we show that hepcidin antimicrobial peptide (Hamp), encoding the hormone hepcidin essential for iron homeostasis and regulated by dietary iron and inflammation, is a target gene of the two SREBP isoforms SREBP-1a/c.Wefound that in tissue culture, mature, active, and nuclear forms of the SREBP-1a/c proteins induce endogenous Hamp gene expression and increase the Hamp promoter activity primarily via three regulatory sequences, including an E-box. Moreover, ChIP experiments revealed that SREBP-1a binds to the Hamp gene promoter. Overexpression of nuclear SREBP-1a under the control of the phosphoenolpyruvate carboxylase-1 (Pck1) promoter in mice increased hepatic Hamp mRNA and blood hepcidin levels, and as expected, caused fatty liver. Consistent with the known effects of Hamp up-regulation, SREBP-1a-overexpressing mice displayed signs of dysregulation in iron metabolism, including reduced serum iron and increased hepatic and splenic iron storage. Conversely, liver-specific depletion of the nuclear forms of SREBPs, as in SREBP cleavage- activating protein knockout mice, impaired lipopolysaccharide- induced up-regulation of hepatic Hamp. Together, these results indicate that the SREBP-1a/c transcription regulators activate hepcidin expression and thereby contribute to the control of mammalian iron metabolism.
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U2 - 10.1074/jbc.RA119.009644
DO - 10.1074/jbc.RA119.009644
M3 - Article
C2 - 31270208
AN - SCOPUS:85071512320
SN - 0021-9258
VL - 294
SP - 12743
EP - 12753
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -