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Journal of Lipid Research, Vol. 49, 2524-2534, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Cholesterol accumulation and diabetes in pancreatic β-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity

Mayumi Ishikawa^2,*, Yuko Iwasaki^2,*, Shigeru Yatoh^*, Toyonori Kato^*, Shin Kumadaki^*, Noriyuki Inoue^*, Takashi Yamamoto^*, Takashi Matsuzaka^*,, Yoshimi Nakagawa^*,, Naoya Yahagi, Kazuto Kobayashi^*, Akimitsu Takahashi^*, Nobuhiro Yamada^* and Hitoshi Shimano^1,*,

^* Department of Internal Medicine (Endocrinology and Metabolism), Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575
Center for Advanced Research Alliance, University of Tsukuba, 1-1-1 Tennodai, Tsukuba-City, Ibaraki, Japan, 305-8575
² M. Ishikawa and Y. Iwasaki contributed equally to this work.

Published, JLR Papers in Press, August 8, 2008.

This work was supported by grants-in-aid from the Ministry of Science, Education, Culture, and Technology of Japan.

¹ To whom correspondence should be addressed. e-mail: shimano-tky{at}umin.ac.jp

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.

Supplementary key words transcription factors • sterol-regulatory element binding protein • triglycerides

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