Summary of Research Project Results under JSPS FY2001
"Research for the Future Program"



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
 
5.Project Number 97L00803
 
6.Title of Project Roles and Disorders of Receptors for Plasma Lipoproteims

7.Project Leader
Name Institution,Department Title of Position
Tokuo Yamamoto Tohoku University, Gene Reseach Center Professor

8.Core Members

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.

10.Key Words

(1)lipoprotein、(2)diabetes、(3)atherosclerosis
(4)oxidized LDL、(5)scavenger recepto、(6)Alzheimer's disease
(7)LDL receptor-related Protein、(8)LOX-1、(9)SR-PSOX


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