Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in Hepatocytes
Hepcidin, a major regulator of systemic iron homeostasis, is mainly induced in hepatocytes by activating bone morphogenetic protein 6 (BMP-6) signaling in response to changes in the iron status. Small heterodimer partner-interacting leucine zipper protein (SMILE), a polyphenol-inducible transcriptio...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-10-01
|
| Series: | Antioxidants |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3921/10/10/1590 |
| _version_ | 1797515406980677632 |
|---|---|
| author | Yu-Ji Kim Woo-Ram Park Byungyoon Choi Hueng-Sik Choi Don-Kyu Kim |
| author_facet | Yu-Ji Kim Woo-Ram Park Byungyoon Choi Hueng-Sik Choi Don-Kyu Kim |
| author_sort | Yu-Ji Kim |
| collection | DOAJ |
| description | Hepcidin, a major regulator of systemic iron homeostasis, is mainly induced in hepatocytes by activating bone morphogenetic protein 6 (BMP-6) signaling in response to changes in the iron status. Small heterodimer partner-interacting leucine zipper protein (SMILE), a polyphenol-inducible transcriptional co-repressor, regulates hepatic gluconeogenesis and lipogenesis. Here, we examine the epigallocatechin-3-gallate (EGCG) effect on BMP-6-mediated SMAD1/5/8 transactivation of the hepcidin gene. EGCG treatment significantly decreased BMP-6-induced hepcidin gene expression and secretion in hepatocytes, which, in turn, abated ferroportin degradation. SMILE overexpression significantly decreased BMP receptor-induced hepcidin promoter activity. SMILE overexpression also significantly suppressed BMP-6-mediated induction of hepcidin mRNA and its secretion in HepG2 and AML12 cells. EGCG treatment inhibited BMP-6-mediated hepcidin gene expression and secretion, which were significantly reversed by SMILE knockdown in hepatocytes. Interestingly, SMILE physically interacted with SMAD1 in the nucleus and significantly blocked DNA binding of the SMAD complex to the BMP-response element on the hepcidin gene promoter. Taken together, these findings suggest that SMILE is a novel transcriptional repressor of BMP-6-mediated hepcidin gene expression, thus contributing to the control of iron homeostasis. |
| first_indexed | 2024-03-10T06:45:03Z |
| format | Article |
| id | doaj.art-1b2ac22c1242433480d83c5b1d58f01e |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-10T06:45:03Z |
| publishDate | 2021-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-1b2ac22c1242433480d83c5b1d58f01e2023-11-22T17:16:22ZengMDPI AGAntioxidants2076-39212021-10-011010159010.3390/antiox10101590Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in HepatocytesYu-Ji Kim0Woo-Ram Park1Byungyoon Choi2Hueng-Sik Choi3Don-Kyu Kim4Department of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, KoreaDepartment of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, KoreaDepartment of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, KoreaSchool of Biological Sciences and Technology, Chonnam National University, Gwangju 61186, KoreaDepartment of Integrative Food, Bioscience and Biotechnology, Chonnam National University, Gwangju 61186, KoreaHepcidin, a major regulator of systemic iron homeostasis, is mainly induced in hepatocytes by activating bone morphogenetic protein 6 (BMP-6) signaling in response to changes in the iron status. Small heterodimer partner-interacting leucine zipper protein (SMILE), a polyphenol-inducible transcriptional co-repressor, regulates hepatic gluconeogenesis and lipogenesis. Here, we examine the epigallocatechin-3-gallate (EGCG) effect on BMP-6-mediated SMAD1/5/8 transactivation of the hepcidin gene. EGCG treatment significantly decreased BMP-6-induced hepcidin gene expression and secretion in hepatocytes, which, in turn, abated ferroportin degradation. SMILE overexpression significantly decreased BMP receptor-induced hepcidin promoter activity. SMILE overexpression also significantly suppressed BMP-6-mediated induction of hepcidin mRNA and its secretion in HepG2 and AML12 cells. EGCG treatment inhibited BMP-6-mediated hepcidin gene expression and secretion, which were significantly reversed by SMILE knockdown in hepatocytes. Interestingly, SMILE physically interacted with SMAD1 in the nucleus and significantly blocked DNA binding of the SMAD complex to the BMP-response element on the hepcidin gene promoter. Taken together, these findings suggest that SMILE is a novel transcriptional repressor of BMP-6-mediated hepcidin gene expression, thus contributing to the control of iron homeostasis.https://www.mdpi.com/2076-3921/10/10/1590SMILEepigallocatechin-3-gallate (EGCG)BMP-6SMAD1/5/8hepcidiniron metabolism |
| spellingShingle | Yu-Ji Kim Woo-Ram Park Byungyoon Choi Hueng-Sik Choi Don-Kyu Kim Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in Hepatocytes Antioxidants SMILE epigallocatechin-3-gallate (EGCG) BMP-6 SMAD1/5/8 hepcidin iron metabolism |
| title | Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in Hepatocytes |
| title_full | Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in Hepatocytes |
| title_fullStr | Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in Hepatocytes |
| title_full_unstemmed | Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in Hepatocytes |
| title_short | Epigallocatechin-3-Gallate Suppresses BMP-6-Mediated SMAD1/5/8 Transactivation of Hepcidin Gene by Inducing SMILE in Hepatocytes |
| title_sort | epigallocatechin 3 gallate suppresses bmp 6 mediated smad1 5 8 transactivation of hepcidin gene by inducing smile in hepatocytes |
| topic | SMILE epigallocatechin-3-gallate (EGCG) BMP-6 SMAD1/5/8 hepcidin iron metabolism |
| url | https://www.mdpi.com/2076-3921/10/10/1590 |
| work_keys_str_mv | AT yujikim epigallocatechin3gallatesuppressesbmp6mediatedsmad158transactivationofhepcidingenebyinducingsmileinhepatocytes AT woorampark epigallocatechin3gallatesuppressesbmp6mediatedsmad158transactivationofhepcidingenebyinducingsmileinhepatocytes AT byungyoonchoi epigallocatechin3gallatesuppressesbmp6mediatedsmad158transactivationofhepcidingenebyinducingsmileinhepatocytes AT huengsikchoi epigallocatechin3gallatesuppressesbmp6mediatedsmad158transactivationofhepcidingenebyinducingsmileinhepatocytes AT donkyukim epigallocatechin3gallatesuppressesbmp6mediatedsmad158transactivationofhepcidingenebyinducingsmileinhepatocytes |