| Budget Amount *help |
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1993: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1992: ¥800,000 (Direct Cost: ¥800,000)
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| Research Abstract |
The metabolic turnover of HDL-apo AI has been studied in order to know the mechanism of low and high plasma HDL levels.
1) We attempted here to determine the kinetic parameters (turnover) of HDL apo AI in normal Japanese White (control) rabbits, with or without cholesterol, probucol and pravastatin feeding. ^<125>l-labeled HDL was injected intraveneously and blood samples were taken periodically for 6 days. Kinetic parameters were calculated from the apo AI specific radioactivity decay curves. We found that the apo AI fractional catabolic rates (FCR) in rabbits fed pravastatin with Ch (group 1) were significantly less than those in rabbits fed pravastatin plus probucol with Ch (group 2) (0.546(〕SY.+-.〔)0.017 /day vs. 0.730(〕SY.+-.〔)0.126 /day, p<0.05), while the synthetic rates (SR) of apo AI was lower in group 2 than in group 1 (14.76(〕SY.+-.〔)1.71 mg/kg/day vs. 11.21(〕SY.+-.〔)2.38 mg/kg/day.respectively, p<0.1) . These data indicate that pravastatin and probucol have different effects
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on HDL-apo AI kinetics in a diet which includes cholesterol. The addition of pravastatin to probucol did not enhance HDL metabolism in this expermental models, but rather reduce the synthesis of Apo AI.Total RNA was isolated from rabbit intestine under various conditions as stated above. Compared to findings in control rabbits, probucol or pravastatin treated rabbits showed no changes in mRNA level of apo AI.
2) In vivo conversion of recombinant human proapoprotein AI (rh-Met-proapo AI) from E.coli to apo AI was also investigated in rabbits in vivo. It was found that the radioactivity of rh-Met-proapo AI migrated to more acidic isoproteins, the conversion was complete within 24 hours. Thus, a) the proteolytic cleavage of proapo AI is an extracellular event, b) the converting enzyme from rabbits is functional for human proapo AI processing, and c) the injection of rh-Met-proapo AI into rabbits facilities understanding of the early events of HDL biogenesis in rabbits.
3) In vivo kinetics of lipoprotein(a) [Lp(a)] were also investigated in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia, and in normolipidemic Japanese White rabbits (controls). The fractional catabolic rates (FCRs) of both Lp(a) and LDL (1.355(〕SY.+-.〔)0.189 pools per day and 1.278(〕SY.+-.〔)0.397 pools per day, respectively) in the WHHL rabbits were significantly (p<0.005) smaller than those in the control rabbits (2-008(〕SY.+-.〔)0.083 pools per day and 2.855(〕SY.+-.〔)0.759 pools per day, respectively) . Our data storongly suggest that Lp(a) clearance is not entirely dependent upon LDL receptors and may be mediated by some other mechanisms.
4) We found six types of apo AI variants. They were radiolabeled and injected into rabbits as above. We found no peculiar pathway for apo AI variants compated to the kinetics of native apo Al(Al_3) . Less
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