| Budget Amount *help |
¥2,300,000 (Direct Cost: ¥2,300,000)
Fiscal Year 1991: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1990: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Research Abstract |
Serum lipoproteins and apo E were analyzed from 199 patients in CCU, having angina pectoris or myocardial infarction, and from 211 healthy subjects. The frequency of apo E4 was higher and that of E2 was lower in the CCU group than in the control group. Apo E mutants, E7 and E5, were also frequent in the CCU group. When we examined serum lipoproteins by the apo E phenotypes, the subjects with an E3/2 phenotype had reduced LDL and increased very low density lipoprotein (VLDL) concentrations, and those with an E4/3 phenotype had increased LDL levels in serum. The results suggested that the E4 and E2 isoproteins were positive and negative risk factors for atherosclerosis, respectively. One of the mechanisms of atherosclerosis is associated with the action of apo E isoproteins on serum LDL levels.
We have previously demonstrated unique isoproteins of apo E (apo E5 and E7) associated with liyperlipidemia and atlierosclerosis. Gene analysis of E5 showed that a G to A substitution had resulted
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in a Glu to Lys substitution at the third position of the mature protein. F, 7 had two G to A substitutions, resulting in -Glu-Glu- to -Lys-Lys- substitution at positions 244 and 245. We characterized the activity of apo E5 and apo E7 binding to LDL receptors on human fibroblasts. The affinity of apo E5 was twice that of wild form of apo E3. Apo E7, however, had a lower receptor affinity than apo E3. The high affinity, of apo E5 may result in a high uptake of apo E5-containing lipoproteins by the liver and lead to a down-regulation of LDL receptors in the liver. We can postulate that the subjects with apo E5 are susceptible to hypercholesterolemia and in consequence to atherosclerosis.
We developed a rapid, accurate, and sensitive method for determining apo E molecular species, and to utilize this method we investigated the relationship between apo E isoproteins and serum lipoprotein metabolism in children. Apo E phenotypes and serum lipoprotein levels were determined in 767 school children aged 7, 10 and 13 years old. Apo E phenotyping was performed by immunoblotting of an isoelectric focusing gel. Serum samples were treated with neuraminidase before delipidation. Serum cholesterol and LDL-cholesterol concentrations increase'd in the order of E3/2 -> 1/2 E3/3 -> E4/3 in each agegroup. The effect of the apo E polymorphism in serum apo B was the same tendency as cholesterol levels, but the opposite effect on serum apo E concentrations was observed. It was noteworthy that the effect of apo E isoforms on serum lipoproteins had been revealed even in childhood. We suggest the possibility that hyperlipoproteinemia and atherosclerosis miglit be prevent by dietary control based on apo E phenotypes early in life. Less
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