Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells
In pancreatic β cells, ABCA1, a 254 kDa membrane protein, affects cholesterol homeostasis and insulin secretion. Angiotensin II, as the main effector of the renin–angiotensin system, decreases glucose-stimulated insulin secretion (GSIS). We examined the effect of angiotensin II on ABCA1 expression i...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2018-10-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520341821 |
| _version_ | 1831691204884955136 |
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| author | Jingya Lyu Hitomi Imachi Kensaku Fukunaga Seisuke Sato Tomohiro Ibata Toshihiro Kobayashi Tao Dong Takuo Yoshimoto Kazuko Yonezaki Hiromi Nagata Hisakazu Iwama Koji Murao |
| author_facet | Jingya Lyu Hitomi Imachi Kensaku Fukunaga Seisuke Sato Tomohiro Ibata Toshihiro Kobayashi Tao Dong Takuo Yoshimoto Kazuko Yonezaki Hiromi Nagata Hisakazu Iwama Koji Murao |
| author_sort | Jingya Lyu |
| collection | DOAJ |
| description | In pancreatic β cells, ABCA1, a 254 kDa membrane protein, affects cholesterol homeostasis and insulin secretion. Angiotensin II, as the main effector of the renin–angiotensin system, decreases glucose-stimulated insulin secretion (GSIS). We examined the effect of angiotensin II on ABCA1 expression in primary pancreatic islets and INS-1 cells. Angiotensin II decreased ABCA1 protein and mRNA; angiotensin II type 1 receptor (AT1R) blockade rescued this ABCA1 repression. In parallel, angiotensin II suppressed the promoter activity of ABCA1, an effect that was abrogated by PD98095, a specific inhibitor of MAPK kinase (MEK). LXR enhanced ABCA1 promoter activity, and angiotensin II decreased the nuclear abundance of LXR protein. On a chromatin immunoprecipitation assay, LXR mediated the transcription of ABCA1 by directly binding to its promoter. Mutation of the LXR binding site on the ABCA1 promoter cancelled the effect of angiotensin II. Furthermore, angiotensin II induced cholesterol accumulation and impaired GSIS; inhibition of AT1R or MEK pathway reversed these effects. In summary, our study showed that angiotensin II suppressed ABCA1 expression in pancreatic islets and INS-1 cells, indicating that angiotensin II may influence GSIS by regulating ABCA1 expression. Additional research may address therapeutic needs in diseases such as diabetes mellitus. |
| first_indexed | 2024-12-20T11:25:44Z |
| format | Article |
| id | doaj.art-67e3f76ce2264de4a596a2c4424d3e6e |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-20T11:25:44Z |
| publishDate | 2018-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-67e3f76ce2264de4a596a2c4424d3e6e2022-12-21T19:42:23ZengElsevierJournal of Lipid Research0022-22752018-10-01591019061915Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cellsJingya Lyu0Hitomi Imachi1Kensaku Fukunaga2Seisuke Sato3Tomohiro Ibata4Toshihiro Kobayashi5Tao Dong6Takuo Yoshimoto7Kazuko Yonezaki8Hiromi Nagata9Hisakazu Iwama10Koji Murao11Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanDepartment of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanLife Science Research Center, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, JapanTo whom correspondence should be addressed.; Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan; To whom correspondence should be addressed.In pancreatic β cells, ABCA1, a 254 kDa membrane protein, affects cholesterol homeostasis and insulin secretion. Angiotensin II, as the main effector of the renin–angiotensin system, decreases glucose-stimulated insulin secretion (GSIS). We examined the effect of angiotensin II on ABCA1 expression in primary pancreatic islets and INS-1 cells. Angiotensin II decreased ABCA1 protein and mRNA; angiotensin II type 1 receptor (AT1R) blockade rescued this ABCA1 repression. In parallel, angiotensin II suppressed the promoter activity of ABCA1, an effect that was abrogated by PD98095, a specific inhibitor of MAPK kinase (MEK). LXR enhanced ABCA1 promoter activity, and angiotensin II decreased the nuclear abundance of LXR protein. On a chromatin immunoprecipitation assay, LXR mediated the transcription of ABCA1 by directly binding to its promoter. Mutation of the LXR binding site on the ABCA1 promoter cancelled the effect of angiotensin II. Furthermore, angiotensin II induced cholesterol accumulation and impaired GSIS; inhibition of AT1R or MEK pathway reversed these effects. In summary, our study showed that angiotensin II suppressed ABCA1 expression in pancreatic islets and INS-1 cells, indicating that angiotensin II may influence GSIS by regulating ABCA1 expression. Additional research may address therapeutic needs in diseases such as diabetes mellitus.http://www.sciencedirect.com/science/article/pii/S0022227520341821liver X receptorMAPK kinase/ERK1/2lipotoxicity |
| spellingShingle | Jingya Lyu Hitomi Imachi Kensaku Fukunaga Seisuke Sato Tomohiro Ibata Toshihiro Kobayashi Tao Dong Takuo Yoshimoto Kazuko Yonezaki Hiromi Nagata Hisakazu Iwama Koji Murao Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells Journal of Lipid Research liver X receptor MAPK kinase/ERK1/2 lipotoxicity |
| title | Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells |
| title_full | Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells |
| title_fullStr | Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells |
| title_full_unstemmed | Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells |
| title_short | Angiotensin II induces cholesterol accumulation and impairs insulin secretion by regulating ABCA1 in beta cells |
| title_sort | angiotensin ii induces cholesterol accumulation and impairs insulin secretion by regulating abca1 in beta cells |
| topic | liver X receptor MAPK kinase/ERK1/2 lipotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520341821 |
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