Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity
To determine the role of cholesterol synthesis in pancreatic β-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in β-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in β-cells resulted in sever...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2008-12-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520345843 |
| _version_ | 1818931517640933376 |
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| author | Mayumi Ishikawa Yuko Iwasaki Shigeru Yatoh Toyonori Kato Shin Kumadaki Noriyuki Inoue Takashi Yamamoto Takashi Matsuzaka Yoshimi Nakagawa Naoya Yahagi Kazuto Kobayashi Akimitsu Takahashi Nobuhiro Yamada Hitoshi Shimano |
| author_facet | Mayumi Ishikawa Yuko Iwasaki Shigeru Yatoh Toyonori Kato Shin Kumadaki Noriyuki Inoue Takashi Yamamoto Takashi Matsuzaka Yoshimi Nakagawa Naoya Yahagi Kazuto Kobayashi Akimitsu Takahashi Nobuhiro Yamada Hitoshi Shimano |
| author_sort | Mayumi Ishikawa |
| collection | DOAJ |
| description | To determine the role of cholesterol synthesis in pancreatic β-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in β-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in β-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was primarily due to defects in glucose- and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esterified cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated expression of HMG-CoA synthase and reductase and LDL receptor, with suppression of endogenous SREBPs. Genes involved in β-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of β-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken together, these results indicate that activation of SREBP-2 in β-cells caused severe diabetes by loss of β-cell mass with accumulation of cholesterol, providing a new lipotoxic model and a potential link of disturbed cholesterol metabolism to impairment of β-cell function. |
| first_indexed | 2024-12-20T04:17:51Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-20T04:17:51Z |
| publishDate | 2008-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-905ef0f75800438893c6430ec36aad022022-12-21T19:53:44ZengElsevierJournal of Lipid Research0022-22752008-12-01491225242534Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicityMayumi Ishikawa0Yuko Iwasaki1Shigeru Yatoh2Toyonori Kato3Shin Kumadaki4Noriyuki Inoue5Takashi Yamamoto6Takashi Matsuzaka7Yoshimi Nakagawa8Naoya Yahagi9Kazuto Kobayashi10Akimitsu Takahashi11Nobuhiro Yamada12Hitoshi Shimano13M. Ishikawa and Y. Iwasaki contributed equally to this work.; Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575M. Ishikawa and Y. Iwasaki contributed equally to this work.; Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575; Center for Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575; Center for Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Center for Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575; Center for Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575To determine the role of cholesterol synthesis in pancreatic β-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in β-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in β-cells resulted in severe diabetes as evidenced by greater than 5-fold elevations in glycohemoglobin compared with C57BL/6 controls. Diabetes in TgRIP-SREBP-2 mice was primarily due to defects in glucose- and potassium-stimulated insulin secretion as determined by glucose tolerance test. Isolated islets of TgSREBP-2 mice were fewer in number, smaller, deformed, and had decreased insulin content. SREBP-2-expressing islets also contained increased esterified cholesterol and unchanged triglycerides with reduced ATP levels. Consistently, these islets exhibited elevated expression of HMG-CoA synthase and reductase and LDL receptor, with suppression of endogenous SREBPs. Genes involved in β-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of β-cell mass, whereas IRS2 expression was not affected. These phenotypes were dependent on the transgene expression. Taken together, these results indicate that activation of SREBP-2 in β-cells caused severe diabetes by loss of β-cell mass with accumulation of cholesterol, providing a new lipotoxic model and a potential link of disturbed cholesterol metabolism to impairment of β-cell function.http://www.sciencedirect.com/science/article/pii/S0022227520345843transcription factorssterol-regulatory element binding proteintriglycerides |
| spellingShingle | Mayumi Ishikawa Yuko Iwasaki Shigeru Yatoh Toyonori Kato Shin Kumadaki Noriyuki Inoue Takashi Yamamoto Takashi Matsuzaka Yoshimi Nakagawa Naoya Yahagi Kazuto Kobayashi Akimitsu Takahashi Nobuhiro Yamada Hitoshi Shimano Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity Journal of Lipid Research transcription factors sterol-regulatory element binding protein triglycerides |
| title | Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity |
| title_full | Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity |
| title_fullStr | Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity |
| title_full_unstemmed | Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity |
| title_short | Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity |
| title_sort | cholesterol accumulation and diabetes in pancreatic β cell specific srebp 2 transgenic mice a new model for lipotoxicity |
| topic | transcription factors sterol-regulatory element binding protein triglycerides |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520345843 |
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