Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: | |
| Zdroj: | Journal of Lipid Research, Vol 49, Iss 12, Pp 2524-2534 (2008) |
| Druh dokumentu: | article |
| ISSN: | 0022-2275 75800438 |
| DOI: | 10.1194/jlr.M800238-JLR200 |
| Popis: | 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. |
| Databáze: | Directory of Open Access Journals |
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