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1996 Fiscal Year Final Research Report Summary

Basic study for analysis and application of bio-factor which regulate transfer of cholresterol in vivo.

Research Project

Project/Area Number 06557128
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section試験
Research Field Biological pharmacy
Research InstitutionUniversity of Tokyo

Principal Investigator

INOUE Keizo  Faculty of Pharmaceutical Sciences, University of Tokyo, Proffesor, 薬学部, 教授 (30072937)

Co-Investigator(Kenkyū-buntansha) SAEKI Takao  Eisai Co, LTD,Tukuba, Research Lab., Senior Reseacher, 研究開発本部, 主任研究員
TOMODA Hirosi  Reserch Center for Biological function, The Kitasato Institute, Chief Director, 細胞化学研究部, 副部長
AOKI Junken  Faculty of Pharmaceutical Sciences, University of Tokyo, Assistant Proffesor, 薬学部, 助手 (20250219)
ARAI Hiroyuki  Faculty of Pharmaceutical Sciences, University of Tokyo, Assosiate Proffesor, 薬学部, 助教授 (40167987)
Project Period (FY) 1994 – 1996
KeywordsChoresterol / CETP / HDL / LDL / Macropage / SRBI
Research Abstract

The lipid-laden foam cells that are typically found in atherosclerotic lesions in the arterial wall are believed to be derived, at least in part, from tissue macrophages that have become engorged with cholesteryl ester-rich lipoproteins. Tissue macrophages themselves are derived from circulating blood monocytes that have entered the subendotherial space. Although the mechanism for the conversion of a subendotherial monocyte to a foam cell is not fully understood, one process that has been proposed to contribute to the accumulation of cellular cholesteryl ester in these cells is the scavenger receptor pathway.
The agents which inhibit cholesteryl ester accumulation in macrophages should be useful in both elucidating mechanism involved in foam cell formation and developing pharmacological drugs to prevent the formation of atherosclerotic plaques. A series of antimycotics were reported to have substantial effects on cellular cholesterol metabolism. The data obtained in the present study de … More monstrate that one of the antimycotics, ketoconazole, effectively inhibit cholesteryl ester synthsis by restricting the movement of endocytosed cholesterol from lysosomes to other cellular sites.
In addition, various steroid derivertives were assessed for their ability to inhibit the cholesteryl ester formation from endocytosed cholesterol by macrophages. Among various steroids tested, one group of steroids having an oxo group at the C17 or C20 position such as pregnenolone, progesterone, androstenedione, and dehydroisoandrosterone completely inhibited cholesteryl ester formation at 10 muM.In contrast, other group of steroids having a hydroxy group at the C17 position such as testosterone and androstenediol had a lesser effect ; complete inhibition for cholesteryl ester formation was achieved at 100 muM or more. The mechanism for the inhibition by the former class of steroids was further studied. These steroids did not block the uptake or lysosomal hydrolysis of liposomes, nor esterification of fatty acyl chains into triacylglycerols. Upon incubation with the steroids having an oxo group at the C17 or C20 position. free cholesterol taken up by the macrophages is likely to be accumulated in phagocytotic vacuoles from cytochemical observation with filipin-cholesterol staining. These results indicate that a series of structurally-related steroids characterized by the presence of an oxo group at the C17 or C20 position inhibit cholesteryl ester formation in macrophages by blocking the intracellular transport of endocytosed cholesterol from lysosomes to endoplasmic reticulum. Less

  • Research Products

    (14 results)

All Other

All Publications (14 results)

  • [Publications] 新井洋由: "コレステロールの細胞内輸送機構" 蛋白質 核酸 酵素. 39. 22-35 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 新井洋由: "ライソゾームH^+-ATPaseの阻害剤" 生体の科学. 46. 256-261 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Aikawa: "Strycture-specific inhibitation of lysosomal cholesterol transport in macrophages by rarious steroids" Biochim.Biophys.Acta. 1213. 127-134 (1994)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Fukasawa: "Chinese hamstar ovary cells expressing a novel type of acetylated low density lipoprotein receptor" J.Biol.Chem.270. 1921-1927 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Sato: "Side-chain Structure is critical for the transport of sterols from lysosomesto sytoplasm" Biochim.Biophys.Acta. 1257. 38-46 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Sato: "Encyme-linked immunosorbent assay for cholosteryl ester transfer protein in human serum" Chin.Chim.Acta. 240. 1-9 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] T.Yamada: "Astroglial localization of cholesteryl ester transfer protein in normal and alzheimer's disease brain tissues" Acta Neuropathol. 90. 633-636 (1995)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Fukasawa: "SRB1,a class B scarenger receptor,recogizes both negatively charged liposomes and apoptotic cells" Exp.Cell Res.222. 246-250 (1996)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Kazuhiro Aikawa: "Strycture-specific inhibitation of lysosomal sholesterol transport in macrophages by various steroids" Biochim. Biophys. Acta.1213. 127-134 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masayoshi Fukasawa: "Chinese hamster ovary cells expressing a novel type of acetylated low density lipoprotein receptor" J.Biol. Chem.270. 1921-1927 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Yuji Sato: "Side-chain structure is critical for the transport of sterols from lysosomes to cytoplasm" Biochim. Biophys. Acta.1257. 38-46 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Toshitaka Sato: "Enzyme-linked immunosorbent assay for cholesteryl ester transfer protein in human serum" Clin. Chim. Acta.240. 1-9 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Tatsuya Yamada: "Astroglial localization of cholesteryl ester transfer protein in normal and alzheimer's disease brain tissues" Acta Neuropathol. 90. 633-636 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Masayoshi Fukasawa: "SRB1, a class B scavenger receptor, recognizes both negatively charged liposomes and apoptotic cells" Exp. Cell Res.222. 246-250 (1996)

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1999-03-09  

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