1999 Fiscal Year Final Research Report Summary
Development of a novel animal model to investigate the role of cholesterol metabolism in the development and differentiation
| Project/Area Number |
10557104
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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 The University of Tokyo, Faculty of Medicine Assist, 医学部・附属病院, 助手 (90212919)
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| Co-Investigator(Kenkyū-buntansha) |
OSUGA Jun-ichi The University of Tokyo, Assistant, 医学部・附属病院, 医員
HARADA Kenji The University of Tokyo, Assistant, 医学部・附属病院, 医員
YAMADA Nobuhiro The University of Tokyo, Associate Professor, 医学部・附属病院, 助教授 (40200729)
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| Project Period (FY) |
1998 – 1999
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| Keywords | Development / Cholesterol / Squalene synthase / Gene targeting / Knockout mouse / Hedgehog / Farneso1 / Neural tube defect |
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| Research Abstract |
Squalene synthase (SS) catalyzes the reductive head-to-head condensation of two molecules of farnesyl diphosphate (FPP) to form squalene, the first specific intermediate in the cholesterol biosynthetic pathway. We used gene targeting to knock out the mouse SS gene. The mice heterozygous for the mutation (SS+/-) were apparently normal. SS+/- mice showed 60% reduction in the hepatic mRNA levels of SS compared to SS+/+mice. Consistently, the SS enzymatic activities were reduced by 50% in the liver and testis. Nevertheless, the hepatic cholesterol synthesis was not different between SS+/- and SS+/+ mice and plasma lipoprotein profiles were not different irrespective of the presence of the LDL receptor, indicating that SS is not a rate-limiting enzyme in the cholesterol biosynthetic pathway. The mice homozygous for the disrupted SS gene (SS-/-) were embryonic lethal around midgestation. E9.5-10.5 SS-/- embryos exhibited severe growth retardation and defective neural tube closure. The lethal phenotype was not rescued by supplementing the dams either with dietary squalene or cholesterol. We speculate that cholesterol is required for the development, particularly, of nervous system, and that the chorioallantoic circulatory system is not mature enough to supply the rapidly growing embryos with maternal cholesterol at this developmental stage.
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[Publications] Tozawa R, Ishibashi S, Osuga J, Yagyu H, Oka T, Chen Z, Ohashi K, Perrey S, Shionoiri F, Yahagi N, Harada K, Gotoda T, Yazaki Y, Yamada: "Embryonic Lethality and Defective Neural Tube Closure in Mice Lacking Squalene Synthase"J. Biol. Chem.. 274. 30843-30848 (1999)
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「研究成果報告書概要(欧文)」より
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[Publications] Yuan X, Ishibashi S, Hatakeyama S, Saito M, Nakayama J, Nikaido R, Haruyama T, Watanabe Y, Iwata H, Iida M, Sugimura H, Yamada N, Ishikawa F.: "The presence of telomeric G-strand tails in the telomerase catalytic subunit TERT knockout mice."Genes Cells. 4. 563-572 (1999)
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[Publications] Yahagi N, Shimano, H, Hasty AH, Amemiya-Kudo M, Okazaki H. Tamura Y, Iizuka Y, Shionoiri F, Ohashi K, Osuga J-I, Harada K, Gotoda T, Nagai R, Ishibashi S, Yamada N.: "A crucial role of sterol regulatory element-binding protein-1 in the regulation of lipogenic gene expression by polyunsaturated fatty acids."J. Biol. Chem.. 274. 35840-335844 (1999)
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[Publications] H Shimano, N Yahagi, M Amemiya-Kudo, AH Hasty, J-i Osuga, Y Tamura, F Shionoiri, Y Iizuka, K Ohashi, K Harada, T Gotoda, S Ishibashi, N Yamada.: "Sterol regulatory element-binding protein-1 as a key transcription factor for nutritional induction of lipogenic enzyme genes."J. Biol. Chem.. 274. 35832-35839 (1999)
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