| First Author | Radhakrishnan K | Year | 2020 |
| Journal | Int J Mol Sci | Volume | 21 |
| Issue | 19 | PubMed ID | 32998264 |
| Mgi Jnum | J:303498 | Mgi Id | MGI:6514471 |
| Doi | 10.3390/ijms21197148 | Citation | Radhakrishnan K, et al. (2020) Orphan Nuclear Receptor ERRgamma Is a Novel Transcriptional Regulator of IL-6 Mediated Hepatic BMP6 Gene Expression in Mice. Int J Mol Sci 21(19):7148 |
| abstractText | 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 gamma (ERRgamma), in response to the pro-inflammatory cytokine interleukin 6 (IL-6). Recombinant IL-6 treatment increases hepatic ERRgamma and BMP6 expression. Overexpression of ERRgamma is sufficient to increase BMP6 gene expression in hepatocytes, suggesting that IL-6 is upstream of ERRgamma. In line, knock-down of ERRgamma in cell lines or a hepatocyte specific knock-out of ERRgamma in mice significantly decreases IL-6 mediated BMP6 expression. Promoter studies show that ERRgamma 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 ERRgamma, GSK5182, markedly inhibits IL-6 induced hepatic BMP6 expression in vitro and in vivo. Taken together, these results reveal a novel molecular mechanism on ERRgamma mediated transcriptional regulation of hepatic BMP6 gene expression in response to IL-6. |
