Abstract
Bone morphogenetic protein 6 (BMP6) is a multifunctional growth factor involved in organ development and homeostasis. BMP6 controls expression of the liver hormone, hepcidin, and thereby plays a crucial role in regulating iron homeostasis. BMP6 gene transcriptional regulation in liver is largely unknown, but would be of great help to externally modulate iron load in pathologic conditions. Here, we describe a detailed molecular mechanism of hepatic BMP6 gene expression by an orphan nuclear receptor, estrogen-related receptor γ (ERRγ), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRγ and BMP6 expression. Overexpression of ERRγ is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRγ. In line, knock-down of ERRγ in cell lines or a hepatocyte specific knock-out of ERRγ in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRγ directly binds to the ERR response element (ERRE) in the mouse BMP6 gene promoter and positively regulates BMP6 gene transcription in IL-6 treatment conditions, which is further confirmed by ERRE mutated mBMP6-luciferase reporter assays. Finally, an inverse agonist of ERRγ, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRγ mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6.
Highlights
Bone morphogenetic proteins (BMPs) are secreted-type growth factors belonging to the transforming growth factor (TGF)-β superfamily, which includes TGF-βs, activins and growth differentiation factors [1,2,3]
Hepatic Bone morphogenetic protein 6 (BMP6)-SMAD signaling plays an important role in iron homeostasis through transcriptionally regulating the liver hormone, hepcidin, which mediates the degradation of iron transporter ferroportin in hepatocytes, macrophages, and enterocytes to control iron entry into the systemic circulation [16,17,18,19]
As we previously reported the interleukin 6 (IL-6) induced hepatic estrogen-related receptor γ (ERRγ) gene up-regulation [32], here we hypothesized that ERRγ may regulate the BMP6 gene expression in hepatocytes
Summary
Bone morphogenetic proteins (BMPs) are secreted-type growth factors belonging to the transforming growth factor (TGF)-β superfamily, which includes TGF-βs, activins and growth differentiation factors [1,2,3]. ERRγ is expressed in several embryonic and adult tissues, especially in tissues with high energy demand such as the heart, brain, kidney, pancreas, and liver It regulates target gene expression by directly binding to extended half-site core sequences referred to as ERR response element (ERRE) (5 -TCAAGGTCA-3 ) as either monomers or dimmers on the regulatory region of the target genes which are primarily involved in cellular metabolism and energy homeostasis [20]. ERRγ plays an important role in glucose, lipids and alcohol metabolism and its hepatic expression is induced in fasting condition [28,29,30,31] It involved in iron homeostasis through regulating the expression of hepatic iron regulating hormone, hepcidin [32]. Hepatocyte specific ERRγ knock-out or treatment with an ERRγ specific inverse agonist GSK5182 inhibited IL-6 induced BMP6 gene expression in hepatocytes
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