| Co-Investigator(Kenkyū-buntansha) |
NAGAI Ryoji Kumamoto University, Biochemistry, Assistant Professor, 医学部, 助手 (20315295)
MIYAZAKI Akira Kumamoto University, Biochemistry, Associate Professor, 医学部, 講師 (70253721)
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| Research Abstract |
Long-term incubation of proteins with glucose leads, through the Schiff base and Amadori product, to the formation of advanced glycation end products (AGE). The biomedical significance of AGE in vivo were studied from three lines of aspects ; (i) identification of major AGE-structures in vivo, (ii) and their localization in tissues and (iii) structural and functional analyses of AGE-receptors.
(i) Identification of major AGE-structures in vivo : Methylglyoxal, which was generated from glycolysis and polyol pathways through the cleavage of gleceraldehyde-3-phosphate, reacted with protein to form the AGE such as N^ε-(carboxyethyl)lysine (CEL). Especially, methylglyoxal was also generated from the cleavage of Schiff base of the Maillard reaction, followed by contribution to further AGE formation.
(ii) Localization of AGE in tissues : Accumulation of N^ε-(carboxymethyl)lysine (CML), one of the major AGE structures, has been identified in pulmonary macrophages in patients with pulmonary fibro
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sis and neuron in patient with familial amyotrophic lateral sclerosis, strongly suggesting that AGE may involve in the pathogenesis of these disease processes.
(iii) Structural and functional analysis of AGE receptor : To evaluate the AGE-receptor expressed in liver endothelial cells (LEC), we also determined whether scavenger receptor class B such as CD-36 and SR-BI, highly expressed in LEC, serve as an AGE receptor. CD-36-overexpressed CHO cells showed endocytic uptake and subsequent intracellular degradation of AGE-proteins, suggesting that AGE-ligands generated in situ are recognized by CD36, which might contribute to the pathogenesis of diabetic macrovascular complications. By using SR-BI-overexpressed CHO cells (SR-BI-CHO), we clearly showed that SR-BI also serves as an AGE receptor involved in endocytic uptake of AGE-proteins. Furthermore, AGE-protein effectively inhibited not only SR-BI-mediated selective uptake of CE from HDL particles, but also HDL-mediated cholesterol efflux from SR-BI-CHO cells, indicating that AGE-ligands play a significant role in the HDL-mediated reverse cholesterol transport in vivo. Less
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