The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression
Farnesoid X receptor (FXR) controls the expression of critical genes in bile acid and cholesterol homeostasis. To study FXR and to develop a regulator of cholesterol, some nonsteroidal and steroidal ligands have been found in addition to endogenous ligands for FXR. In this study, we discovered five...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2008-01-01
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| Series: | Journal of Pharmacological Sciences |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S134786131931415X |
| _version_ | 1818976012710445056 |
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| author | Takuo Suzuki Norimasa Tamehiro Yoji Sato Tetsu Kobayashi Akiko Ishii-Watabe Youichi Shinozaki Tomoko Nishimaki-Mogami Toshihiro Hashimoto Yoshinori Asakawa Kazuhide Inoue Yasuo Ohno Teruhide Yamaguchi Toru Kawanishi |
| author_facet | Takuo Suzuki Norimasa Tamehiro Yoji Sato Tetsu Kobayashi Akiko Ishii-Watabe Youichi Shinozaki Tomoko Nishimaki-Mogami Toshihiro Hashimoto Yoshinori Asakawa Kazuhide Inoue Yasuo Ohno Teruhide Yamaguchi Toru Kawanishi |
| author_sort | Takuo Suzuki |
| collection | DOAJ |
| description | Farnesoid X receptor (FXR) controls the expression of critical genes in bile acid and cholesterol homeostasis. To study FXR and to develop a regulator of cholesterol, some nonsteroidal and steroidal ligands have been found in addition to endogenous ligands for FXR. In this study, we discovered five bile acid derivatives (methyl cholate, methyl deoxycholate, 5β-cholanic acid, 5β-cholanic acid-7α,12α-diol, and NIHS700) and two natural products (marchantin A and marchantin E) that activated FXR in the reporter assay. These compounds activated FXR to a high level comparable to the most potent endogenous bile acid, chenodeoxycholic acid, although it was not predicted from their structures; five of them were similar to the lower potency bile acids, and two were structurally much different from bile acids. The elevation levels of reporter gene expression by some of the screened compounds were varied in Cos-7, HepG2, HuH-7, and Caco-2 cells. These compounds also controlled the expression of genes regulated by FXR, and some of the compounds regulated these genes in a cell-type–specific and/or gene-selective fashion. Therefore, molecular design of the compounds can cause selective modulation of the expression of FXR target genes. Keywords:: farnesoid X receptor (FXR), reporter assay, ginkgolic acid, marchantin, cell-type–specific modulation |
| first_indexed | 2024-12-20T16:05:05Z |
| format | Article |
| id | doaj.art-54ff935b5140480fbae8dfdb6020a717 |
| institution | Directory Open Access Journal |
| issn | 1347-8613 |
| language | English |
| last_indexed | 2024-12-20T16:05:05Z |
| publishDate | 2008-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Pharmacological Sciences |
| spelling | doaj.art-54ff935b5140480fbae8dfdb6020a7172022-12-21T19:34:11ZengElsevierJournal of Pharmacological Sciences1347-86132008-01-011073285294The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene ExpressionTakuo Suzuki0Norimasa Tamehiro1Yoji Sato2Tetsu Kobayashi3Akiko Ishii-Watabe4Youichi Shinozaki5Tomoko Nishimaki-Mogami6Toshihiro Hashimoto7Yoshinori Asakawa8Kazuhide Inoue9Yasuo Ohno10Teruhide Yamaguchi11Toru Kawanishi12Division of Biological Chemistry and Biologicals, Tokyo 158-8501, Japan; Pharmaceuticals and Medical Device Agency, Tokyo 100-0013, Japan; Corresponding author (affiliation #1). tsuzuki@nihs.go.jpDivision of Biosignaling, Tokyo 158-8501, JapanDivision of Cellular and Gene Therapy Products, Tokyo 158-8501, JapanDivision of Biological Chemistry and Biologicals, Tokyo 158-8501, JapanDivision of Biological Chemistry and Biologicals, Tokyo 158-8501, JapanDivision of Pharmacology, National Institute of Health Sciences, Tokyo 158-8501, JapanDivision of Biosignaling, Tokyo 158-8501, JapanFaculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, JapanFaculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima 770-8514, JapanGraduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, JapanDivision of Pharmacology, National Institute of Health Sciences, Tokyo 158-8501, JapanDivision of Biological Chemistry and Biologicals, Tokyo 158-8501, JapanDivision of Biological Chemistry and Biologicals, Tokyo 158-8501, JapanFarnesoid X receptor (FXR) controls the expression of critical genes in bile acid and cholesterol homeostasis. To study FXR and to develop a regulator of cholesterol, some nonsteroidal and steroidal ligands have been found in addition to endogenous ligands for FXR. In this study, we discovered five bile acid derivatives (methyl cholate, methyl deoxycholate, 5β-cholanic acid, 5β-cholanic acid-7α,12α-diol, and NIHS700) and two natural products (marchantin A and marchantin E) that activated FXR in the reporter assay. These compounds activated FXR to a high level comparable to the most potent endogenous bile acid, chenodeoxycholic acid, although it was not predicted from their structures; five of them were similar to the lower potency bile acids, and two were structurally much different from bile acids. The elevation levels of reporter gene expression by some of the screened compounds were varied in Cos-7, HepG2, HuH-7, and Caco-2 cells. These compounds also controlled the expression of genes regulated by FXR, and some of the compounds regulated these genes in a cell-type–specific and/or gene-selective fashion. Therefore, molecular design of the compounds can cause selective modulation of the expression of FXR target genes. Keywords:: farnesoid X receptor (FXR), reporter assay, ginkgolic acid, marchantin, cell-type–specific modulationhttp://www.sciencedirect.com/science/article/pii/S134786131931415X |
| spellingShingle | Takuo Suzuki Norimasa Tamehiro Yoji Sato Tetsu Kobayashi Akiko Ishii-Watabe Youichi Shinozaki Tomoko Nishimaki-Mogami Toshihiro Hashimoto Yoshinori Asakawa Kazuhide Inoue Yasuo Ohno Teruhide Yamaguchi Toru Kawanishi The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression Journal of Pharmacological Sciences |
| title | The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression |
| title_full | The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression |
| title_fullStr | The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression |
| title_full_unstemmed | The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression |
| title_short | The Novel Compounds That Activate Farnesoid X Receptor: the Diversity of Their Effects on Gene Expression |
| title_sort | novel compounds that activate farnesoid x receptor the diversity of their effects on gene expression |
| url | http://www.sciencedirect.com/science/article/pii/S134786131931415X |
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