2000 Fiscal Year Annual Research Report

メイラード反応後期生成物(AGE)の構造と生物医学的意義に関する研究

Research Project

Project/Area Number	10044305
Research Institution	Kumamoto University
Principal Investigator	堀内正公熊本大学, 医学部, 教授 (10117377)
Co-Investigator(Kenkyū-buntansha)	永井竜児熊本大学, 医学部, 助手 (20315295) 宮崎章熊本大学, 医学部, 講師 (70253721)
Keywords	メイラード反応 / AGE / グリケーション / 動脈硬化症 / 糖尿病合併症
Research Abstract	(1)AGEの主要構造体の決定とその生物医学的意義の検討:平成12年度は、ヒトの体液(血液及び尿中)中に生成するAGE構造体について解析を行った結果、既知のAGE構造体の一つであるpentosidineと類似した構造を有するCreatin-pentosidineが同定された。Creatin-pentosidineの構造をNMR及びGC/MSで詳細に解析した結果、クレアチンとリジンがリボースによって架橋された構造を有することが明らかとなった。腎機能の低下によって血中クレアチンレベルが上昇するが、今回の研究から、クレアチンより架橋性AGEが生成し、 (2)肝臓類洞細胞に発現する新規AGE受容体の解析:既に我々は、macrophage scavenger receptor class A (SR-A)が、主要なAGE受容体として機能していることを明らかにしているが、本年度は肝臓内皮細胞(LEC)にはSR-A以外のAGE受容体が存在することを明らかにした。さらに、LECに発現する新規AGE受容体を解析した結果、酸化LDL受容体として知られるCD-36及び、HDL受容体として知られるSR-BIがAGE受容体としても機能していることが明らかとなった。特に、HDLはSR-BIを介してコレステロールを細胞内へ取り込み、あるいは細胞内のコレステロールをHDLへ転送する機能を有しているが、AGE化蛋白は、HDLのSR-BIへの結合は阻害しないのに対して、コレステロールの輸出入を阻害することが明らかとなった。本結果より、糖尿病状態で増加した血中AGEは、SR-BIを介したコレステロールの転送系を阻害し、最終的に動脈硬化を惹起する可能性が示唆された。 (3)メチルグリオキサールに由来する主要AGE構造体の決定と生体内局在:現在までメチルグリオキサールは主として細胞内の解糖系より生成すると考えられてきたが、今回、メイラード反応の中間体であるシッフ塩基からも生成することが、蛍光ラベル法を用いたHPLCによる解析から明らかとなり、さらに、生成したメチルグリオキサールによってCEL及びimidazoloneが生成することが明らかとなった。特にCELは、非糖尿病患者の各所(小腸、肝臓、動脈等)にも存在することから、生体では解糖系のみならず、メイラード反応由来のメチルグリオキサールがAGE生成に関与している可能性が示唆された。

Research Products

(21 results)

All Other

All Publications (21 results)

[Publications] Ohgami N et al.,: "Scavenger receptor classB type I-mediated reverse cholesterol transport is inhibited by advanced glycation end product"J.Biol.Chem.. (In press). (2001)
[Publications] Meng J et al.,: "Tissue carboxymethyllysine in diabetic and non-diabetic patients with chronic renal failure : relevance to glycoxidation damage."Nephron.. (In press). (2000)
[Publications] Kyu-Kyu M et al.,: "Induction of acyl-coenzyme A : cholesterol acyltransferase-1 by 1,25-dihydroxyvitamin D3 or 9-cis-retinoic acid in undifferentiated THP-1 cells"J.Lipid Res.. (In press). (2001)
[Publications] Ohgami N et al.,: "CD36, a member of class B scavenger receptor family, as a receptor for advanced glycation end products (AGE) ."J.Biol.Chem.. 276. 3195-3202 (2001)
[Publications] Sakata N et al.,: "Possible involvement of altered RGD sequence in reduced adhesive and spreading activities of advanced glycation end product-modified fibronectin to vascular smooth muscle cells."Connective Tissue Research. (In press). (2000)
[Publications] Amano S et al.,: "Advanced glycation end products in human optic nerve head"Br J.Ophthalmol.. 85. 52-55 (2001)
[Publications] Iwashima Y et al.,: "Advanced glycation end products-induced gene expression of scaven receptors in cultured human monocyte-derived macrophages."Biochem.Biophys.Res.Commun.. 277. 368-380 (2000)
[Publications] Matsumoto K et al.,: "Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor-A (MSR-A) ."Biochem.J.. 352. 233-240 (2000)
[Publications] Hamada Y et al.,: "Epalrestat, an aldose reductase inhibitor,reduces the levels of Ne- (carboxymethy) lysine protein adducts and their precursors in erythrocytes from diabetic patients"Diabetes Care. 23. 1539-1544 (2000)
[Publications] Ohgami N et al.,: "Glibenclamide acts as an inhibitor of acyl-CoA : cholesterol acyltransferase (ACAT) enzyme"Biochem.Biophys.Res.Commum.. 277. 417-422 (2000)
[Publications] Nagai R et al.,: "Glycolaldehyde, a reactive intermediate for advanced glycation endproducts, plays an important role in the generation of an active ligand for the macrophage scavenger receptor."Diabetes. 49. 1714-1723 (2000)
[Publications] Miyazaki A et al.,: "Granulocyte macrophage colony-stimulating factor plays a priming role in murine macroph growth induced by oxidized low density lipoprotein."Ann.N.Y.Acad.Sci.. 902. 342-342 (2000)
[Publications] Abiko A et al.,: "Increased levels of advanced glycosylation end products in the kidney and liver from spontaneously diabetic Chinese hamsters determined by immunochemical assay."Metabolism.. 49. 567-573 (2000)
[Publications] Nyhlin N et al.,: "Advanced glycation end product in familial amyloidotic polyneuropathy (FAP) ."J.Int.Med.. 247. 485-492 (2000)
[Publications] Kato S et al.,: "Advanced glycation endproduct-modified superoxide dismutase-1 (SOD1) -positive inclusions are common to familial amyotrophic lateral Sclerosis patients with SOD1 gene mutations and transgenic mice expressing human SOD1 with G85R mutation."Neuropathol. 100. 490-505 (2000)
[Publications] Shibata N et al.,: "Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation"Acta Neuropathol. 100. 275-284 (2000)
[Publications] Imanaga Y et al.,: "in vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques."Atherosclerosis. 150. 343-355 (2000)
[Publications] Uesugi N et al.,: "Glycoxidative modification of AA amyloid deposits in renal tissue."Nephrol.Dial.Transplant.. 15. 355-365 (2000)
[Publications] Biwa T et al.,: "Sites of action of protein kinase C and phosphatidylinositol 3-kinase are distinct from oxidized low density lipoprotein-induced macrophage proliferation."J.Biol.Chem.. 275. 5810-5816 (2000)
[Publications] Sakashita N et al.,: "Localization of human acyl-Coenzyme A : cholesterol acyltransferas-1 (ACAT-1) in macrophages and in various tissues."Am.J.Pathol.. 156. 227-236 (2000)
[Publications] Kaji Y et al.,: "Advaced glycation end products in diabetic corneas."Invest.Ophthalmol.Vis.Sci.. 41. 362-368 (2000)

2000 Fiscal Year Annual Research Report

メイラード反応後期生成物(AGE)の構造と生物医学的意義に関する研究

Principal Investigator

堀内 正公 熊本大学, 医学部, 教授 (10117377)

Research Products

[Publications] Ohgami N et al.,: "Scavenger receptor classB type I-mediated reverse cholesterol transport is inhibited by advanced glycation end product"J.Biol.Chem.. (In press). (2001)

[Publications] Meng J et al.,: "Tissue carboxymethyllysine in diabetic and non-diabetic patients with chronic renal failure : relevance to glycoxidation damage."Nephron.. (In press). (2000)

[Publications] Kyu-Kyu M et al.,: "Induction of acyl-coenzyme A : cholesterol acyltransferase-1 by 1,25-dihydroxyvitamin D3 or 9-cis-retinoic acid in undifferentiated THP-1 cells"J.Lipid Res.. (In press). (2001)

[Publications] Ohgami N et al.,: "CD36, a member of class B scavenger receptor family, as a receptor for advanced glycation end products (AGE) ."J.Biol.Chem.. 276. 3195-3202 (2001)

[Publications] Sakata N et al.,: "Possible involvement of altered RGD sequence in reduced adhesive and spreading activities of advanced glycation end product-modified fibronectin to vascular smooth muscle cells."Connective Tissue Research. (In press). (2000)

[Publications] Amano S et al.,: "Advanced glycation end products in human optic nerve head"Br J.Ophthalmol.. 85. 52-55 (2001)

[Publications] Iwashima Y et al.,: "Advanced glycation end products-induced gene expression of scaven receptors in cultured human monocyte-derived macrophages."Biochem.Biophys.Res.Commun.. 277. 368-380 (2000)

[Publications] Matsumoto K et al.,: "Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor-A (MSR-A) ."Biochem.J.. 352. 233-240 (2000)

[Publications] Hamada Y et al.,: "Epalrestat, an aldose reductase inhibitor,reduces the levels of Ne- (carboxymethy) lysine protein adducts and their precursors in erythrocytes from diabetic patients"Diabetes Care. 23. 1539-1544 (2000)

[Publications] Ohgami N et al.,: "Glibenclamide acts as an inhibitor of acyl-CoA : cholesterol acyltransferase (ACAT) enzyme"Biochem.Biophys.Res.Commum.. 277. 417-422 (2000)

[Publications] Nagai R et al.,: "Glycolaldehyde, a reactive intermediate for advanced glycation endproducts, plays an important role in the generation of an active ligand for the macrophage scavenger receptor."Diabetes. 49. 1714-1723 (2000)

[Publications] Miyazaki A et al.,: "Granulocyte macrophage colony-stimulating factor plays a priming role in murine macroph growth induced by oxidized low density lipoprotein."Ann.N.Y.Acad.Sci.. 902. 342-342 (2000)

[Publications] Abiko A et al.,: "Increased levels of advanced glycosylation end products in the kidney and liver from spontaneously diabetic Chinese hamsters determined by immunochemical assay."Metabolism.. 49. 567-573 (2000)

[Publications] Nyhlin N et al.,: "Advanced glycation end product in familial amyloidotic polyneuropathy (FAP) ."J.Int.Med.. 247. 485-492 (2000)

[Publications] Shibata N et al.,: "Nonoxidative protein glycation is implicated in familial amyotrophic lateral sclerosis with superoxide dismutase-1 mutation"Acta Neuropathol. 100. 275-284 (2000)

[Publications] Imanaga Y et al.,: "in vivo and in vitro evidence for the glycoxidation of low density lipoprotein in human atherosclerotic plaques."Atherosclerosis. 150. 343-355 (2000)

[Publications] Uesugi N et al.,: "Glycoxidative modification of AA amyloid deposits in renal tissue."Nephrol.Dial.Transplant.. 15. 355-365 (2000)

[Publications] Biwa T et al.,: "Sites of action of protein kinase C and phosphatidylinositol 3-kinase are distinct from oxidized low density lipoprotein-induced macrophage proliferation."J.Biol.Chem.. 275. 5810-5816 (2000)

[Publications] Sakashita N et al.,: "Localization of human acyl-Coenzyme A : cholesterol acyltransferas-1 (ACAT-1) in macrophages and in various tissues."Am.J.Pathol.. 156. 227-236 (2000)

[Publications] Kaji Y et al.,: "Advaced glycation end products in diabetic corneas."Invest.Ophthalmol.Vis.Sci.. 41. 362-368 (2000)

堀内正公熊本大学, 医学部, 教授 (10117377)