Cell-biological and molecular biological analyzes of reverse cholesterol transport as a protective system against atherosclerosis

点击翻译按钮获取中文摘要

I.Analysis of abnormal function of lipoproteins in cholesteryl ester transfer protein (CETP) deficiencyLipoprotein 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 deficiencyWe 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 … More revealed to be as common as the intron 14 splicing defect in Japan.III.Atherogenicity in CETP deficiencyThe 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 transportWe 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