Cholesterol accumulation and diabetes in pancreatic beta-cell-specific SREBP-2 transgenic mice: a new model for lipotoxicity.
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.
Ishikawa
Mayumi
M
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.
Iwasaki
Yuko
Y
Yatoh
Shigeru
S
Kato
Toyonori
T
Kumadaki
Shin
S
Inoue
Noriyuki
N
Yamamoto
Takashi
T
Matsuzaka
Takashi
T
Nakagawa
Yoshimi
Y
Yahagi
Naoya
N
Kobayashi
Kazuto
K
Takahashi
Akimitsu
A
Yamada
Nobuhiro
N
Shimano
Hitoshi
H
D000818:Animals; D002784:Cholesterol / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D051381:Rats; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics* / Q000378:metabolism
D007328:Insulin; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol