1994 Fiscal Year Final Research Report Summary
Reaction mechanism of cholesterol transport system
| Project/Area Number |
05044173
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| Research Category |
Grant-in-Aid for international Scientific Research
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| Allocation Type | Single-year Grants |
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| Section | Joint Research |
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| Research Institution | Kagawa Medical School |
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Principal Investigator |
ICHIKAWA Yoshiyuki Kagawa, Medical School, Professor, 医学部, 教授 (60028355)
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| Co-Investigator(Kenkyū-buntansha) |
YAMAMURA Taku Research Institute of National Cardiovascular Center, Head, 病因部, 室長 (20132938)
YAMAMOTO Akira Research Institute of National Cardiovascular Center, Vice Director, 副所長 (00028408)
YOKOYAMA Shinji University of Alberta, Professor, 医学部, 教授 (10142192)
OHNISHI Taira Kagawa, Medical School, Associate Professor, 医学部, 助教授 (50211107)
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| Project Period (FY) |
1993 – 1994
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| Keywords | Cholesterol Reverse Transport System / Apolipoprotein / Lipid Microemulsion / Lipid Microemulsion / Pyrene Compound / Vascular smooth muscle cell / Cholesterol efflux / Discoidal Highdensity Plasma Lipoprotein |
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| Research Abstract |
The initial step of reverse cholesterol transport from peripheral cells to liver cells is the efflux of cholesterol from peripheral cells. We revealed that the addition of free apolipoprotein induces the efflux of cholesterol from macrophage and smooth muscle cells and free apolipoprotein is incorporated into newly synthesized discoidal HDL-like particle. At the next step, free cholesterol is converted to cholesteryl ester by LCAT and then cholesteryl ester is transferred among various lipoproteins by plasma lipid transfer protein (LTP). In this term, our study of reverse cholesterol transport was focused on the action of LCAT and the effect of apolipoproteins on the LTP reaction.
We revealed that the LTP reaction requires the presence of apolipoprotein (A-I,A-II,C-III and E)on the surface of lipid particle and the mode of integration of apolipoprotein into the surface lipid regulates the lipid selectivity of the LTP reaction. In addition, the effect of A-IV on the LTP reaction was also
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studied and the effect was revealed to be essentially the same as other apolipoproteins.
We prepared the monoclonal antibody against rabbit LTP,and we found the special clone which inhibit only triglyceride transfer by LTP.To clarify the structural basis of lipid selectivity of LTP,we decided to use molecular biological approach to characterize LTP.The cDNA of rabbit LTP was prepared and LTP was expressed in the yeast system. We are going to characterize the epitope of the clone using the expression system.
The transfer of free cholesterol between cell and HDL is thought to be concentration-dependent on the basis of equilibrium. The conversion of free cholesterol into cholesteryl ester by LTP causes the decrease of the concentration of free cholesterol in HDL and the decrease gives the driving force to the reverse cholesterol system. Our study revealed that the addition of LCAT into the macrophage system, where cholesterol efflux from cell is mediated by discoidal HDL-like particle or HDL,induces the decrease of free cholesterol and increase of cholesteryl ester in HDL,however, efflux of cholesterol remains to be unchanged. Further study must be necessary to establish the new theory of the mechanism of cholesterol efflux. Less
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