Animal model for metabolic syndrome and its molecular basis.

代谢综合征动物模型及其分子基础。

• 批准号: 16390260
• 负责人: YAMADA Nobuhiro
• 金额: $ 9.22万
• 依托单位: University of Tsukuba
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390260/
• 关键词: Metabolic syndrome; Insulin sensitivity; transcription factor; Diabetes; SREBP

Insulin receptor substrate 2 (IRS-2) is the main mediator of insulin signalling in the liver, controlling insulin sensitivity. Sterol regulatory element binding proteins (SREBPs) have been established as transcriptional regulators of lipid synthesis. Here, we show that SREBPs directly repress transcription of IRS-2 and inhibit hepatic insulin signalling. The IRS-2 promoter is activated by forkhead proteins through an insulin response element (IRE). Nuclear SREBPs effectively replace and interfere in the binding of these transactivators, resulting in inhibition of the downstream PI(3)K/Akt pathway, followed by decreased glycogen synthesis. These data suggest a molecular mechanism for the physiological switching from glycogen synthesis to lipogenesis and hepatic insulin resistance that is associated with hepatosteatosis.

胰岛素受体底物2(IRS-2)是肝脏胰岛素信号的主要介体，控制胰岛素敏感性。固醇调节元件结合蛋白(SREBPs)已被确定为脂类合成的转录调节蛋白。在这里，我们表明，SREBPs直接抑制IRS-2的转录，并抑制肝脏胰岛素信号。IRS-2启动子由叉头蛋白通过胰岛素反应元件(IRE)激活。核SREBPs有效地取代和干扰这些反式激活剂的结合，导致下游的PI(3)K/Akt途径被抑制，随后糖原合成减少。这些数据表明，肝脏骨质疏松症与肝脏胰岛素抵抗有关，从糖原合成到脂肪生成的生理性转换是一种分子机制。

项目成果

Scavenger receptor expressed by endothelial cells I (SREC-I) mediates the uptake of acetylated low density lipoproteins by macrophages stimulated with lipopolysaccharide

• DOI: 10.1074/jbc.m313088200
• 发表时间: 2004-07-23
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Tamura, Y;Osuga, J;Ishibashi, S
• 通讯作者: Ishibashi, S

P53 involvement in the pathogenesis of fatty liver disease

• DOI: 10.1074/jbc.m400884200
• 发表时间: 2004-05-14
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Yahagi, N;Shimano, H;Yamada, N
• 通讯作者: Yamada, N

High mobility group protein-B1(MGB1)interacts with sterol reguatory element-binding proteins(SEBPs) to enhance their DNA binding.

高迁移率族蛋白-B1 (MGB1) 与甾醇调节元件结合蛋白 (SEBP) 相互作用以增强其 DNA 结合。

• 发表时间: 2005
• 期刊: J Biol Chem 280(30)
• 作者: Najima Y;et al.
• 通讯作者: et al.

Lipid synthetic transcription factor SREBP-1a activates p21WAF1/CIP1, a universal cyclin-dependent kinase inhibitor

• DOI: 10.1128/mcb.25.20.8938-8947.2005
• 发表时间: 2005-10-01
• 期刊: MOLECULAR AND CELLULAR BIOLOGY
• 影响因子: 5.3
• 作者: Inoue, N;Shimano, H;Yamada, N
• 通讯作者: Yamada, N

Sterol regulatory element-binding proteins activate insulin gene promoter directly and indirectly through synergy with BETA2/E47

• DOI: 10.1074/jbc.m506718200
• 发表时间: 2005-10-14
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Amemiya-Kudo, M;Oka, J;Shimano, H
• 通讯作者: Shimano, H