| First Author | Ishikawa M | Year | 2008 |
| Journal | J Lipid Res | Volume | 49 |
| Issue | 12 | Pages | 2524-34 |
| PubMed ID | 18682608 | Mgi Jnum | J:143133 |
| Mgi Id | MGI:3822964 | Doi | 10.1194/jlr.M800238-JLR200 |
| Citation | Ishikawa M, et al. (2008) Cholesterol accumulation and diabetes in pancreatic beta-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity. J Lipid Res 49(12):2524-34 |
| abstractText | To determine the role of cholesterol synthesis in pancreatic beta-cells, a transgenic model of in vivo activation of sterol-regulatory element binding protein 2 (SREBP-2) specifically in beta-cells (TgRIP-SREBP-2) was developed and analyzed. Expression of nuclear human SREBP-2 in beta-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 beta-cell differentiation, such as PDX1 and BETA2, were suppressed, explaining loss of beta-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 beta-cells caused severe diabetes by loss of beta-cell mass with accumulation of cholesterol, providing a new lipotoxic model and a potential link of disturbed cholesterol metabolism to impairment of beta-cell function. |
