| Project/Area Number |
09470225
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内分泌・代謝学
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| Research Institution | Kumamoto University |
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Principal Investigator |
HORIUCHI Seikoh Department of Biochemistry, Kumamoto University School of Medicine, Professor, 医学部, 教授 (10117377)
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| Co-Investigator(Kenkyū-buntansha) |
ARAKI Eiichi Department of Metabolic Medicine, Kumamoto University School of Medicine, Lectur, 医学部・附属病院, 講師 (10253733)
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| Project Period (FY) |
1997 – 1998
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| Project Status |
Completed (Fiscal Year 1998)
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| Budget Amount *help |
¥13,200,000 (Direct Cost: ¥13,200,000)
Fiscal Year 1998: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 1997: ¥9,200,000 (Direct Cost: ¥9,200,000)
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| Keywords | advanced glycation end products (AGF) / diabetic complications / macrophage / scavenger receptor / insulin / intracellular signal transduction / P13 kinase / insulin receptor / スカベンジャー受容体 / lyn / MAP kinase / AGE / スカベンジャー受容体(MSR) / インスリン受容体(HIR) |
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| Research Abstract |
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.
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