1998 Fiscal Year Final Research Report Summary
Enhancement of cellular cholesterol efflux and atherosclerosis treatwent by pharmacological stimulation of an apolipoprotein receptor(s)
| Project/Area Number |
09557081
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
内分泌・代謝学
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| Research Institution | Nagoya City University |
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Principal Investigator |
YOKOYAMA Sinji Nagoya City University, Medical School, professor, 医学部, 教授 (10142192)
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| Co-Investigator(Kenkyū-buntansha) |
TSUJITA Maki Nagoya City University, Medical School, research associate, 医学部, 助手 (10253262)
ABE-DOHMAE Sumiko Nagoya City University, Medical School, assistant professor, 医学部, 講師 (70227700)
ITO Jinichi Nagoya City University, Medical School, assistant professor, 医学部, 講師 (60167260)
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| Project Period (FY) |
1997 – 1998
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| Keywords | Cholesterol / HDL / Apolipoprotein / Cell / Signal Transduction |
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| Research Abstract |
Two independent mechanisms are known for cellular cholesterol removal ; physicochemical diffusion and apolipoprotein-cell interaction that causes HDL neogenesis. This research project focused on the latter pathway to achieve the results as follows. 1) Mouse monocytic leukemia cell line cells RAW264 require cAMP for apolipoprotein-mediated HDL generation, and naphthalene sulfonamides known as calmodulin inhibitors enhanced the HDL generation in this condition. This effect was unique to these compounds, being not shared with other calmodulin inhibitors. 2) In vivo regulation of plasma HDL level by the apolipoprotein-mediated HDL generation was studied by using the mice fed with probucol that inhibits the cell/apolipoprotein interaction. Probucol remarkably reduces the HDL level within 2 weeks without changing apoA-I biosynthesis and the plasma HDL clearance rate. Peritoneal macrophages obtained from these animals lost the apoA-I binding, HDL generation and the reactive intracellular cholesterol trafficking. Therefore, reduction of HDL cholesterol was shown to be due to the lack of apolipoprotein/cell interaction, a model for Tangier disease. 3) When the apolipoprotein-mediated HDL generation was blocked by probucol in the LCAT knock-out mice in which non-specific diffusion mediated efflux of cell cholesterol is impaired, cholesterol accumulated in certain organs as the liver and thymus.
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