1999 Fiscal Year Final Research Report Summary
Generation of the lecithin : cholesterol acyltransferase (LCAT) knockout mouse and the investigation of the relation between LCAT and atherosclerosis.
| Project/Area Number |
10671067
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Osaka University |
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Principal Investigator |
SAKAI Naohiko Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (80294073)
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| Co-Investigator(Kenkyū-buntansha) |
HIRANO Kenichi Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
FUNAHASHI Toru Osaka University Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (60243234)
YAMASHITA Shizuya Osaka University Graduate School of Medicine, Lecturer, 医学系研究科, 講師 (60243242)
NISHIDA Makoto Osaka University Hospital, Medical Staff, 医学部・附属病院, 医員
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| Project Period (FY) |
1998 – 1999
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| Keywords | lecithin : cholesterol acyltransferase (LCAT) / atherosclerosis / HDL metabolism / reverse cholesterol transport / renal dysfunction / lipoprotein X (LpX) / corneal opacities |
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| Research Abstract |
To investigate the relation between LCAT and atherosclerosis we have generated the LCAT knockout (LCAT-KO) mouse using gene targeting in the ES cells. In homozygous LCAT-KO mice, the levels of plasma total cholesterol (23% of normal value), HDL-C (7%) and apo A-I (14%) were decreased compared with those in control mice, whereas plasma triglyceride level was increased (212%) in LCAT-KO mice. Electron microscopic analyses revealed the existence of rouleaux formation of discoid HDL, abnormal form of lipoproteins in VLDL and LDL fractions and LpX which is usually seen in the plasma of human LCAT deficient patients. Thus, LACT plays an pivotal role not only in the HDL metabolism but also in the apo B-containing lipoprotein metabolism. The Oil red O and filipin stainings of the renal tissues from the homozygous LCAT-KO mice demonstrated that free cholesterol were deposited in the glomeruli, which might be one of the causes of renal dysfunction in the LCAT deficiency. To obtain the LCAT-KO mice with homogeneous background of C57BL/6J, LCAT-KO mice were backcrossed to C57BL/6J mice for several generation. To analyze the susceptibility to atherosclerosis in LCAT-KO mice, homozygous and heterozygous LCAT-KO mice as well as normal mice were fed high fat, high cholesterol diet (15% fat 1.25% cholesterol, 0.5% cholic acid) for 16 weeks. The histological analyses of the ascending aorta in those mice after the feeding showed that the atherosclerotic plaques increased as the activity of LCAT was decreased, suggesting that LCAT activity is atherogenic in mice which lack plasma CETP activity. Further histological and biochemical studies are in progress as to the mechanisms by which LCAT deficiency causes atherosclerosis and renal dysfunction in relation to the abnormality in the lipid and lipoprotein metabolisms.
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Research Products
(13 results)
