Grant-in-Aid for General Scientific Research (A)
|Allocation Type||Single-year Grants|
|Research Institution||Osaka University|
MATSUZAWA Yuji Professor and Chairman, 2nd Dep Intern Med, Osaka Univ Med Sch, 医学部, 教授 (70116101)
松澤 佑次 大阪大学, 医学, 教授
HIRAOKA Hisatoyo Medical Staff, 2nd Dep Intern Med, Osaka Univ Hosp, 医学部・附属病院, 医員
NAZAKI Shuichi Associate Professor, 2nd Dep Intern Med, Osaka Univ Med Sch, 医学部, 助手 (30252646)
YAMASHITA Shizuya Associate Professor, 2nd Dep Intern Med, Osaka Univ Med Sch, 医学部, 助手 (60243242)
TAKEMURA Kaoru Associate Professor, 2nd Dep Intern Med, Osaka Univ Med Sch, 医学部, 助手 (00161240)
TOKUNAGA Katsuto Associate Professor, 2nd Dep Intern Med, Osaka Univ Med Sch, 医学部, 助手 (70159044)
平野 賢一 大阪大学, 医学部・附属病院, 医員
酒井 尚彦 大阪大学, 医学部附属病院, 医員
船橋 徹 大阪大学, 医学部, 助手
|Project Period (FY)
1992 – 1993
Completed(Fiscal Year 1993)
|Budget Amount *help
¥31,500,000 (Direct Cost : ¥31,500,000)
Fiscal Year 1993 : ¥12,000,000 (Direct Cost : ¥12,000,000)
Fiscal Year 1992 : ¥19,500,000 (Direct Cost : ¥19,500,000)
|Keywords||Reverce cholesterol transport / High density lipoproteins / Cholesteryl ester transfer protein / Hyperalphalipoproteinemia / Hepatic triglyceride phase / Aherosclerosis / Primary biliary cirrhosis / Reverse Cholesterol Transport(コレステロール逆転送系) / Hyperalphaliroproteinemia(高HPL血症) / Cholesteryl Ester Transfer Protein(コレステリルエステル転送蛋白) / High Dousity Lipoprotein(高比重リポ蛋白) / コレステロールエステル転送蛋白 / 分子生物学 / 細胞生物学|
I.Analysis of abnormal function of lipoproteins in cholesteryl ester transfer protein (CETP) deficiency
Lipoprotein abnormalities in CETP deficiency were characterized by the presence of large and cholesteryl-ester(CE)-rich HDL and small polydisperse LDL.Large and CE-rich HDL_2 obtained from homozygous CETP-deficient subjects was less effective for reducing cholesterol content in lipid-laden macrophages than that from control subjects. The small polydisperse LDL of patients had reduced affinity for the LDL receptor of normal human fibroblasts. These abnormal in vitro function of plasma lipoproteins from CETP deficiency may be associated with athrosclerosis.
II.Molecular basis of CETP deficiency
We found that the frequency of the G-to-A mutation at the 5' splice donor slite of intron 14 in the CETP gene was approximately 1% in the Japanese general population. We also found a novel missense mutation in exon 15(D442 ; G) in markedly hyperalphalipoproteinemic patients. This novel mutation was
revealed to be as common as the intron 14 splicing defect in Japan.
III.Atherogenicity in CETP deficiency
The hyperalphalipoproteinemic subjects with coronary heart disease (CHD) and juvenile corneal opacification (Atherosclerosis 53 ; 207-212, 1984), were identified to be homozygous for the exon 15 missense mutation. We also found that CETP-deficient patients with low HTGL may be susceptible to CHD.
We found a unique area where a marked hyperalphalipoproteinemia (HALP) caused by the intron 14 splicing defect was markedly accumulated. In this area, a marked HALP and the intron 14 CETP gene mutation were less frequentry observed in the eiderly survived subjects than in the younger subjects. These results suggested that CETP deficiency may not be a longevity syndrome.
IV.Lipoprotein abnormalities in primary biliary cirrhosis (PBC)
PBC was known to be often associated with HALP and xanthomas.We found that plasma levels of CETP were markedly increased and HTGL activities were reduced in hyperalphalipoproteinemic patients with PBC, in contrast to CETP deficincy.
V.Interaction between HDL and hepatocytes, a terminal of reverce cholesterol transport
We found that HDL is taken up and degraded by a human hepatoma cell line, Mahlavu, in contrast to extrahepatic peripheral cells, in which the degradation of HDL does not occur. The results indicated that HDL-associated cholesterol may be processed via a pathway different from that of LDL metabolism. Less