Development of a novel animal model to investigate the role of cholesterol metabolism in the development and differentiation

开发一种新型动物模型来研究胆固醇代谢在发育和分化中的作用

基本信息

批准号：
10557104
负责人：
ISHIBASHI Shun
金额：
$ 8.7万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

项目摘要

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.

角鲨烯合酶 (SS) 催化法呢基二磷酸 (FPP) 两个分子的头对头还原缩合，形成角鲨烯，角鲨烯是胆固醇生物合成途径中的第一个特定中间体。我们使用基因打靶来敲除小鼠 SS 基因。突变（SS+/-）杂合的小鼠显然是正常的。与 SS+/+ 小鼠相比，SS+/- 小鼠的 SS 肝脏 mRNA 水平降低了 60%。肝脏和睾丸中的 SS 酶活性一致降低了 50%。然而，SS+/- 和 SS+/+ 小鼠之间的肝脏胆固醇合成没有差异，并且无论是否存在 LDL 受体，血浆脂蛋白谱也没有差异，这表明 SS 不是胆固醇生物合成途径中的限速酶。 SS 基因（SS-/-）被破坏的纯合小鼠在妊娠中期胚胎死亡。 E9.5-10.5 SS-/-胚胎表现出严重的生长迟缓和有缺陷的神经管闭合。通过向母鼠补充膳食角鲨烯或胆固醇并不能挽救致命表型。我们推测胆固醇是发育所必需的，特别是神经系统的发育，并且绒毛膜尿囊循环系统还不够成熟，无法在这个发育阶段为快速生长的胚胎提供母体胆固醇。

项目成果

期刊论文数量（22）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Gotoda T, Iizuka Y, Kato N, Osuga J, Bihoreau MT, Murakami T, Yamori Y, Shimano H, Ishibashi S. Yamada N.: "Absence of Cd36 mutation in the original spontaneously hypertensive rats with insulin resistance."Nat. Genet.. 22. 226-228 (1999)

Gotoda T、Iizuka Y、Kato N、Osuga J、Bihoreau MT、Murakami T、Yamori Y、Shimano H、Ishibashi S. Yamada N.：“具有胰岛素抵抗的原始自发性高血压大鼠中不存在 Cd36 突变。”Nat。

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Tozawa R,Ishibashi S,et al.: "Embryonic lethality and defective neural tube closure in mice lacking squalene synthase"J.Biol.Chem.. 274. 30843-30848 (1999)

Tozawa R，Ishibashi S，et al.：“缺乏角鲨烯合酶的小鼠的胚胎致死性和神经管闭合缺陷”J.Biol.Chem.. 274. 30843-30848 (1999)

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Shimano H, Ishibashi S, et al.: "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)

Shimano H，Ishibashi S，等人：“甾醇调节元件结合蛋白-1作为脂肪生成酶基因营养诱导的关键转录因子”J。

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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

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.：“端粒 G 链尾部的存在