2001 Fiscal Year Final Research Report Summary
New therapeutic targets for atherosclerotic plaques - The role of acyl CoA : cholesterol acyltransferase and neutral cholesterol ester hydrolase in foam cell formation
| Project/Area Number |
12557092
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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 |
Metabolomics
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| Research Institution | The University of Tokyo |
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Principal Investigator |
ISHIBASHI Shun University of Tokyo, Department of Metabolic Diseases, Associate, 医学部・附属病院, 助手 (90212919)
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| Co-Investigator(Kenkyū-buntansha) |
HARADA Kenji University of Tokyo, Department of Metabolic Diseases, 医学部・附属病院, 医員
GOTODA Takanari Tokyo Women's Medical College, Diabetes Center, Associate, 糖尿病センター, 助手 (60322062)
SHIMANO Hitoshi University of Tsukuba, Institute of Clinical Medicine, Lecturer, 臨床医学系内科, 講師 (20251241)
OHASHI Ken University of Tokyo, Department of Metabolic, Diseases, 医学部・附属病院, 医員
OSUGA Jun-ichi University of Tokyo, Department of Metabolic, Associate, 医学部・附属病院, 医員
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| Project Period (FY) |
2000 – 2001
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| Keywords | atherosclerosis / gene targeting / adenovirus / ACAT / hormone-sensitive lipase |
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| Research Abstract |
Cholesterol-ester (CE)-laden foam cells are a hallmark of atherosclerosis. Cholesterol is in a dynamic equilibrium between free and esterified form. The esterification and hydrolysis are mediated by acyl CoA : cholesterol acyltransferase (ACAT) and neutral cholesterol ester hydrolase (NCEH), respectively. In the current study, we investigated the role of ACAT-1, an ACAT isoform, and hormone-sensitive lipase (HSL) responsible for NCEH in foam cell formation and atherogenesis.
We have generated ACAT-1 null (ACAT-1-/-) mice, which had decreased openings of the eyes because of atrophy of the meibomian glands, a modified form of sebaceous glands normally expressing high ACAT activities. To determine the role of ACAT-1 in atherogenesis, we crossed the ACAT-1-/- mice with mice lacking apolipoprotein (apo) E or the low density lipoprotein receptor (LDLR), hyperlipidemic models susceptible to atherosclerosis. High fat feeding resulted in extensive cutaneous xanthomatosis with loss of hair in both ACAT-1/-:apoE-/- and ACAT-1-/-:LDLR-/- mice. Free cholesterol content was significantly increased in their skin. Aortic fatty streak lesion size as well as cholesterol ester content were moderately reduced in both mutant mice compared with their respective controls. These results indicate that the local inhibition of ACAT activity in tissue macrophages is protective against cholesteryl ester accumulation but causes cutaneous xanthomatosis in mice lacking apo E or LDLR. Furthermore, we generated HSL-null (HSL-/-) mice, whose macrophages had a substantial activity of NCEH compared with those of wild-type. Consistently, lack of HSL did not aggravate the accumulation of CE in macrophages. Thus, it is rational that HSL is not the primary enzyme for NCEH in macrophages. However, adenoviral mediated overexpression of HSL markedly reduced the CE accumulation through accelerated hydrolysis of CE and decreased uptake of modified lipoproteins.
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[Publications] Yagyu H, Kitamine T, Osuga J, Tozawa R, Chen Z, Kaji Y, Oka T, Perrey S, Tamura Y, Ohashi K, Okazaki H, Yahagi N, Shionoiri F, Iizuka Y, Harada K, Shimano H, Yamashita H, Gotoda T, Yamada N, Ishibashi S: "Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia"J Biol Chem. 275. 21324-21330 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Osuga J, Ishibashi S, Oka T, Yagyu H, Tozawa R, Fujimoto A, Shionoiri F, Yahagi N, Kraemer F B, Tsutsumi O, Yamada N: "Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity"Proc Natl Acad Sci U S A. 97. 787-792 (2000)
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「研究成果報告書概要(欧文)」より
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[Publications] Perrey S, Ishibashi S, Kitamine T, Osuga J, Yagyu H, Chen Z, Shionoiri F, Iizuka Y, Yahagi N, Tamura Y, Ohashi K, Harada K, Gotoda T, Yamada N: "The LDL receptor is the major pathway for beta-VLDL uptake by mouse peritoneal macrophages"Atherosclerosis. 154. 51-60 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Chen Z, Ishibashi S, Perrey S, Osuga J, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N: "Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice : pleiotropic effects on CD36 expression and HDL"Arterioscler Thromb Vase Biol. 21. 372-377 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Tozawa R, Ishibashi S, Osuga J, Yamamoto K, Yagyu H, Ohashi K, Tamura Y, Yahagi N, Iizuka Y, Okazaki H, Harada K, Gotoda T, Shimano H, Kimura S, Nagai R, Yamada N: "Asialoglycoprotein receptor deficiency in mice lacking the major receptor subunit. Its obligate requirement for the stable expression of oligomeric receptor"J Biol Chem. 276. 12624-12628 (2001)
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「研究成果報告書概要(欧文)」より
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[Publications] Ohashi K, Ishibashi S, Osuga J, Tozawa R, Harada K, Yahagi N, Shionoiri F, Iizuka Y, Tamura Y, Nagai R, Illingworth D R, Gotoda T, Yamada N: "Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia"J Lipid Res. 41. 1199-1204 (2000)
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「研究成果報告書概要(欧文)」より
