Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells
Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists rosiglitazone and pioglitazone against Cushing’s disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR-γ agonist, MEK...
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| Format: | Article |
| Language: | English |
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Wiley
2018-01-01
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| Series: | PPAR Research |
| Online Access: | http://dx.doi.org/10.1155/2018/5346272 |
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| author | Rehana Parvin Erika Noro Akiko Saito-Hakoda Hiroki Shimada Susumu Suzuki Kyoko Shimizu Hiroyuki Miyachi Atsushi Yokoyama Akira Sugawara |
| author_facet | Rehana Parvin Erika Noro Akiko Saito-Hakoda Hiroki Shimada Susumu Suzuki Kyoko Shimizu Hiroyuki Miyachi Atsushi Yokoyama Akira Sugawara |
| author_sort | Rehana Parvin |
| collection | DOAJ |
| description | Although therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists rosiglitazone and pioglitazone against Cushing’s disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR-γ agonist, MEKT1, on Pomc expression/ACTH secretion using murine corticotroph-derived AtT20 cells and compared its effects with those of rosiglitazone and pioglitazone. AtT20 cells were treated with either 1 nM~10 μM MEKT1, rosiglitazone, or pioglitazone for 24 hours. Thereafter, their effects on proopiomelanocortin gene (Pomc) mRNA expression were studied by qPCR and the Pomc promoter (−703/+58) activity was demonstrated by luciferase assay. Pomc mRNA expression and promoter activity were significantly inhibited by MEKT1 at 10 μM compared to rosiglitazone and pioglitazone. SiRNA-mediated PPAR-γ knockdown significantly abrogated MEKT1-mediated Pomc mRNA suppression. ACTH secretion from AtT20 cells was also significantly inhibited by MEKT1. Deletion/point mutant analyses of Pomc promoter indicated that the MEKT1-mediated suppression was mediated via NurRE, TpitRE, and NBRE at −404/-383, −316/-309, and −69/-63, respectively. Moreover, MEKT1 significantly suppressed Nur77, Nurr1, and Tpit mRNA expression. MEKT1 also was demonstrated to inhibit the protein-DNA interaction of Nur77/Nurr1-NurRE, Tpit-TpitRE, and Nur77-NBRE by ChIP assay. Taken together, it is suggested that MEKT1 could be a novel therapeutic medication for Cushing’s disease. |
| format | Article |
| id | doaj-art-6de8fcced2d142a3a7a51badca5df7f1 |
| institution | Kabale University |
| issn | 1687-4757 1687-4765 |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | PPAR Research |
| spelling | doaj-art-6de8fcced2d142a3a7a51badca5df7f12025-02-03T05:53:43ZengWileyPPAR Research1687-47571687-47652018-01-01201810.1155/2018/53462725346272Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 CellsRehana Parvin0Erika Noro1Akiko Saito-Hakoda2Hiroki Shimada3Susumu Suzuki4Kyoko Shimizu5Hiroyuki Miyachi6Atsushi Yokoyama7Akira Sugawara8Department of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanDepartment of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanDepartment of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanDepartment of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanDepartment of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanDepartment of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanDrug Discovery Initiative, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, JapanDepartment of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanDepartment of Molecular Endocrinology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, JapanAlthough therapeutic effects of the peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists rosiglitazone and pioglitazone against Cushing’s disease have been reported, their effects are still controversial and inconsistent. We therefore examined the effects of a novel PPAR-γ agonist, MEKT1, on Pomc expression/ACTH secretion using murine corticotroph-derived AtT20 cells and compared its effects with those of rosiglitazone and pioglitazone. AtT20 cells were treated with either 1 nM~10 μM MEKT1, rosiglitazone, or pioglitazone for 24 hours. Thereafter, their effects on proopiomelanocortin gene (Pomc) mRNA expression were studied by qPCR and the Pomc promoter (−703/+58) activity was demonstrated by luciferase assay. Pomc mRNA expression and promoter activity were significantly inhibited by MEKT1 at 10 μM compared to rosiglitazone and pioglitazone. SiRNA-mediated PPAR-γ knockdown significantly abrogated MEKT1-mediated Pomc mRNA suppression. ACTH secretion from AtT20 cells was also significantly inhibited by MEKT1. Deletion/point mutant analyses of Pomc promoter indicated that the MEKT1-mediated suppression was mediated via NurRE, TpitRE, and NBRE at −404/-383, −316/-309, and −69/-63, respectively. Moreover, MEKT1 significantly suppressed Nur77, Nurr1, and Tpit mRNA expression. MEKT1 also was demonstrated to inhibit the protein-DNA interaction of Nur77/Nurr1-NurRE, Tpit-TpitRE, and Nur77-NBRE by ChIP assay. Taken together, it is suggested that MEKT1 could be a novel therapeutic medication for Cushing’s disease.http://dx.doi.org/10.1155/2018/5346272 |
| spellingShingle | Rehana Parvin Erika Noro Akiko Saito-Hakoda Hiroki Shimada Susumu Suzuki Kyoko Shimizu Hiroyuki Miyachi Atsushi Yokoyama Akira Sugawara Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells PPAR Research |
| title | Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells |
| title_full | Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells |
| title_fullStr | Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells |
| title_full_unstemmed | Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells |
| title_short | Inhibitory Effects of a Novel PPAR-γ Agonist MEKT1 on Pomc Expression/ACTH Secretion in AtT20 Cells |
| title_sort | inhibitory effects of a novel ppar γ agonist mekt1 on pomc expression acth secretion in att20 cells |
| url | http://dx.doi.org/10.1155/2018/5346272 |
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