|1.Research Institution||Tohoku University|
|2.Research Area||Life Sciences|
|3.Research Field||Genetic and Environmental Factors in Diseases Prevalent in Adults and the Elderly：Molecular and Cellular Mechanism of Vascular Complications|
|4.Term of Project||FY 1997 〜 FY 2001|
|6.Title of Project||Roles and Disorders of Receptors for Plasma Lipoproteims|
|Name||Institution,Department||Title of Position|
|Tokuo Yamamoto||Tohoku University, Gene Reseach Center||Professor|
|Names||Institution,Department||Title of Position|
|Noriaki Kume||Kyoto University, Graduate School of Medical||Lecturer|
|Takahiro Fujino||Tohoku University, Gene Reseach Center||Assistant research|
9.Summary of Research Results
Disorder of lipoprotein metabolism is pathopysiologically linked with common diseases including atherosclerosis, diabetes and obesity. To elucidate the roles of receptors that bind apoE-contaning lipoproteins, we have been characterizing several LDL receptor related proteins (LRP), including VLDL receptor, apoE receptor 2 and LRP5. To evaluate the function of LRP5 in the development and cholesterol metabolism, we generated mice carrying a mutated LRP5 gene. Mice heterozygous and homozygous for LRP5 deficiency develop hypercholesterolemia when they fed a western-type diet containing high fat and high cholesterol. Under a normal diet, heterozygous and homozygous LRP5 deficiency caused impaired glucose tolerance in mice. In additions, we also identified a novel HDL binding protein. Molecular characterization of this newly identified protein revealed that it is a GPI-anchored protein having a distinct ligand biding specificity from that of a well-characterized HDL receptor, SR-B1.
Lectin-like oxidized LDL receptor (LOX)-1 and scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) are type II and I membrane glycoprtoeins, respectively, both of which can act as cell-surface endocytosis receptors for atherogenic exidized LDL (Ox-LDL). LOX-1 expression can dynamically be induced by proinflammatory stimuli, and is detectable in cultured macrophages and activated vascular smooth muscle cells (VSMC), in addition to endothelial cells. LOX-1-dependent uptake of Ox-LDL induced apoptosis of cultured VSMC. In vivo, endothelial cells that cover early atherosclerotic lesions, and intimal macrophages and VSMC in advanced atherosclerotic plaques dominantly express LOX-1. LOX-1 expressed on the cell-surface can be cleaved, in part, and released as soluble molecules, suggesting a diagnostic role of plasma soluble LOX-1 levels. SR-PSOX appeared to be identical to CXCL16, a novel membrane-anchored chemokine directed to CXCR6-positive lymphocytes, suggesting another role as T-cell chemoattractant. In contrast to LOX-1 expressed by a variety of cell types, SR-PSOX expression appeared relatively confined to macrophages in atherogenesis. Taken together, LOX-1 and SR-PSOX may play important roles in atherogenesis and atherosclerotic plaque rupture.
(4)oxidized LDL、(5)scavenger recepto、(6)Alzheimer's disease
(7)LDL receptor-related Protein、(8)LOX-1、(9)SR-PSOX