Biological clearance system for advanced glycation end products (AGE) -Insulin signal regulates endocytic uptake of AGE-proteins

晚期糖基化终末产物 (AGE) 的生物清除系统 - 胰岛素信号调节 AGE 蛋白的内吞摄取

基本信息

  • 批准号:
    09470225
  • 负责人:
  • 金额:
    $ 8.45万
  • 依托单位:
  • 依托单位国家:
    日本
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
  • 财政年份:
    1997
  • 资助国家:
    日本
  • 起止时间:
    1997 至 1998
  • 项目状态:
    已结题

项目摘要

In Maillard reaction, glucose or reduced sugar reacts with proteins to form Schiff base and Amadori products. These early products are then converted to advanced glycation end products (AGE). AGE-modified proteins are characterized physicochemically by fluorescence, brown color and cross-linking, and biologically by specific recognition by AGE-receptors. Among three proposed AGE-receptors, we demonstrated that MSR-A (macrophage scavenger receptor class A) plays a major role in endocytic uptake of AGE-proteins by macrophages and macrophage-derived cells. AGE-proteins are known to underwent a rapid plasma clearance upon intravenous injection, which was explained by efficient endocytic uptake of liver sinusoidal endothelial cells. In vitro experiment showed that efficient endocytic uptake of AGE-proteins by these cells was enhanced by the presence of insulin. To investigate the mechanism for insulin-enhanced endocytic uptake of AGE-proteins, we constructed CHO cells which were overexpressed both by MSR-A and HIR (human insulin receptor). Endocytic uptake of AGE-proteins by these transfected cells was enhanced by insulin in a dose-dependent manner, whereas CHO cells overexpressed with both MSR-A and mutant HIR did not show the insulin-dependency. Furthermore, insulin-enhanced endocytic uptake of AGE-proteins by these CHO cells was inhibited by PI3 kinase inhibitors such as wortmannin and LY294002, but not by rapamysin, a pp7OS6 kinase inhibitor which was located down stream of PI3 kinase. Insulin did not affect the number of MSR-A on the cell surface of these cells. These results indicate that insulin binding to insulin receptor followed by intracellular signal pathway from IRS-1 to PI3 kinase plays a major role in the insulin-enhanced endocytic uptake of AGE-proteins, probably by increasing the rate of endocytic turnover of MSR-A-mediated endocytic uptake of AGE-proteins.
在美拉德反应中,葡萄糖或还原糖与蛋白质反应生成席夫碱和Amadori产物。这些早期产物随后转化为晚期糖基化终产物(AGE)。AGE修饰的蛋白质在物理化学上以荧光、棕色和交联为特征,在生物学上以AGE受体的特异性识别为特征。在三种建议的AGE受体中,我们证明了MSR-A(巨噬细胞清道夫受体A类)在巨噬细胞和巨噬细胞衍生细胞对AGE蛋白的内吞摄取中起着重要作用。已知AGE-蛋白在静脉注射后经历快速血浆清除,这通过肝窦内皮细胞的有效内吞摄取来解释。体外实验表明,这些细胞对AGE-蛋白的有效内吞摄取通过胰岛素的存在而增强。为了研究胰岛素增强AGE-蛋白的内吞摄取的机制,我们构建了同时过表达MSR-A和HIR(人胰岛素受体)的CHO细胞。胰岛素以剂量依赖性方式增强这些转染细胞对AGE蛋白的内吞摄取,而MSR-A和突变HIR过表达的CHO细胞未显示胰岛素依赖性。此外,胰岛素增强的这些CHO细胞对AGE-蛋白的内吞摄取被PI 3激酶抑制剂如渥曼青霉素和LY 294002抑制,但不被位于PI 3激酶下游的pp 7 OS 6激酶抑制剂rapamysin抑制。胰岛素不影响这些细胞表面MSR-A的数量。这些结果表明,胰岛素与胰岛素受体结合,随后是从IRS-1到PI 3激酶的细胞内信号通路,在胰岛素增强的AGE-蛋白的内吞摄取中起主要作用,可能是通过增加MSR-A介导的AGE-蛋白的内吞摄取的内吞周转率。

项目成果

期刊论文数量(0)
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Takayuki Higashi et al.: "The receptor for advanced glycation end products mediates the chemotaxis of rabbit smooth muscle cells" Diabetes. 46. 463-472 (1997)
Takayuki Higashi 等人:“晚期糖基化终产物受体介导兔平滑肌细胞的趋化性”糖尿病。
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    0
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Imai, N.et al.: "Histological localization of advanced glycosylation end products in the progression of diabetic nephropathy" Nephron. 76. 153-160
Imai, N.et al.:“糖尿病肾病进展中高级糖基化终产物的组织学定位”肾单位。
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    0
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Ikeda, K.et al.: "Determination of glycated albumin by enzyme-linked boronate-immunoassay (ELBIA)" Clin.Chem.442. 256-263 (1998)
Ikeda, K.等人:“通过酶联硼酸盐免疫测定 (ELBIA) 测定糖化白蛋白”Clin.Chem.442。
  • DOI:
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  • 影响因子:
    0
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  • 通讯作者:
Kasuyoshi Ikeda et al.: "Immunochemical approaches to AGE-structures:characterization of anti-AGE antibodies" J.Immunol.Methods. 215. 95-104 (1998)
Kasuyoshi Ikeda 等人:“AGE 结构的免疫化学方法:抗 AGE 抗体的表征”J.Immunol.Methods。
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  • 发表时间:
  • 期刊:
  • 影响因子:
    0
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  • 通讯作者:
Noriyuki Sakata et al.: "Immunohistochemical localization of different epitopes of advanced glycation end products in human atherosclerotic lesions" Atherosclerosis. 141. 61-75 (1998)
Noriyuki Sakata 等人:“人类动脉粥样硬化病变中晚期糖基化终产物的不同表位的免疫组织化学定位”。
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    0
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HORIUCHI Seikoh其他文献

HORIUCHI Seikoh的其他文献

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{{ truncateString('HORIUCHI Seikoh', 18)}}的其他基金

Roles of CD36 and SR-BI as novel AGE-receptors
CD36 和 SR-BI 作为新型 AGE 受体的作用
  • 批准号:
    13470228
  • 财政年份:
    2001
  • 资助金额:
    $ 8.45万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
AGE Structures and their Biomedical Significance
AGE 结构及其生物医学意义
  • 批准号:
    10044305
  • 财政年份:
    1999
  • 资助金额:
    $ 8.45万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A).
Role of AGE Receptors in Diabetic Complications
AGE 受体在糖尿病并发症中的作用
  • 批准号:
    11557081
  • 财政年份:
    1999
  • 资助金额:
    $ 8.45万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B).
Molecular Biology of Acyl-coenzyme A : cholesterol Acyltransferase
酰基辅酶 A 的分子生物学:胆固醇酰基转移酶
  • 批准号:
    08044304
  • 财政年份:
    1996
  • 资助金额:
    $ 8.45万
  • 项目类别:
    Grant-in-Aid for international Scientific Research
Detemination of The Main Advanced Glycation End Product of The Maillard Reaction and Its Significance as A Biochemical Marker for Diabetic Complications
美拉德反应主要高级糖基化终产物的测定及其作为糖尿病并发症生化标志物的意义
  • 批准号:
    07557076
  • 财政年份:
    1995
  • 资助金额:
    $ 8.45万
  • 项目类别:
    Grant-in-Aid for Scientific Research (A)
Structure and Function of Receptors for Advanced Glycation End Products of the Maillard Reaction
美拉德反应高级糖基化终产物受体的结构和功能
  • 批准号:
    06454170
  • 财政年份:
    1994
  • 资助金额:
    $ 8.45万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (B)
Non-enzymatic glycosylation of proteins in biological sytem and its physiological significance in aging process.
生物系统中蛋白质的非酶糖基化及其在衰老过程中的生理意义。
  • 批准号:
    62570136
  • 财政年份:
    1987
  • 资助金额:
    $ 8.45万
  • 项目类别:
    Grant-in-Aid for General Scientific Research (C)

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靶向 RAGE/DIAPH1:糖尿病并发症的新治疗策略
  • 批准号:
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滑膜关节病理的组织芯片建模:炎症和脂肪介导的糖尿病并发症的影响
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醛糖还原酶在糖尿病并发症中的作用
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靶向 RAGE-mDia1 治疗糖尿病并发症:机制和治疗
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