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

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.

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

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

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

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