Development of animal models for atherosclerosis and obesity, and molecular mechanism of the common pathway

动脉粥样硬化和肥胖动物模型的建立及其共同途径的分子机制

• 批准号: 09557079
• 负责人: YAMADA Nobuhiro
• 金额: $ 7.49万
• 依托单位: 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: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557079/
• 关键词: atherosclerosis; obesity; hormone-sensitive lipase; knockout mouse

We intend to study the mechanism of lipid accumulation in arterial wall and fat tissue by studying intracellular lipid metabolism, to clarify the common pathophysiology of atherosclerosis, obesity, hyperlipidemia, and glucose tolerance. As a candidate of insulin-sensitive gene concerning the lipid accumulation which is commonly observed in arteriosclerosis, obesity, and hyperlipidemia, we paid attention to hormone sensitive lipase(HSL)and neutral cholesterol ester hydrolase(NCEH)which may be identical in the regulation of intracellular cholesterol metabolism and triglyceride metabolim. In this study, we try to clarify the common mechanism for atherosclerosis and obesity by gene targeting of HSL.We had already succeeded in gene targeting of HSL, and the series of the HSL knockout mouse was established. The male infertility was recognized when the phenotype of the HSL knockout mouse was analyzed. It was indicated that HSL was related to the spermatogenesis. The obvious lowering of plasma FFA level was not recognized, though the blood FFA level decreased, indicating that novel neutral fat degrading enzyme except for HSL exists in fat tissue. The pathophysiology of obesity, insulin resistance, and glucose tolerance in this mouse model will be examined.

我们打算通过研究细胞内脂质代谢来研究动脉壁和脂肪组织中脂质积聚的机制，以阐明动脉粥样硬化、肥胖、高脂血症和糖耐量的共同病理生理学。激素敏感脂酶(HSL)和中性胆固醇酯水解酶(NCEH)作为胰岛素敏感基因的候选基因，在调节细胞内胆固醇代谢和甘油三酯代谢方面可能是一致的。在本研究中，我们试图通过HSL基因打靶来阐明动脉粥样硬化和肥胖的共同机制。我们已经成功地进行了HSL基因打靶，并建立了HSL基因敲除小鼠系列。通过对HSL基因敲除小鼠的表型分析，可识别为雄性不育。提示HSL与精子发生有关。血浆FFA水平虽有下降，但未见明显下降，表明脂肪组织中存在除HSL外的新型中性脂肪降解酶。在这个小鼠模型中，将检测肥胖、胰岛素抵抗和葡萄糖耐量的病理生理学。

项目成果

山田信博,大橋健 他: "A truncated species of apolipoprotein B(B-38.7)in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus" Arterioscler Thromb Vasc Biol.18. 1330-1334 (1998)

Nobuhiro Yamada、Ken Ohashi 等人：“患有与糖尿病相关的纯合性低β脂蛋白血症的患者中载脂蛋白 B (B-38.7) 的截短种类”Arterioscler Thromb Vasc Biol.1330-1334 (1998)。

Y Watanabe, N Yamada, H Yokoi, Y Fujiwara, H Mokuno, H Daoda, H Yamaguchi: "Relationship between HLA-C locus and restenosis after coronary artery balloon angioplasty." JAMA. 277. 983-984 (1997)

Y Watanabe、N Yamada、H Yokoi、Y Fujiwara、H Mokuno、H Daoda、H Yamaguchi：“HLA-C 位点与冠状动脉球囊血管成形术后再狭窄之间的关系。”

J Osuga, M Yonemoto, N Yamada, H Shimano, H Yagyu, K Ohashi, K Harada, T Kamei, Y Yazaki, S Ishibashi: "Cholesterol lowering in low density lipoprotein receptor knockout mice overexpressing apolipoprotein E." J Clin Invest. 102. 386-394 (1998)

J Osuga、M Yonemoto、N Yamada、H Shimano、H Yagyu、K Ohashi、K Harada、T Kamei、Y Yazaki、S Ishibashi：“过度表达载脂蛋白 E 的低密度脂蛋白受体敲除小鼠中的胆固醇降低。”

K Ohashi, S Ishibashi, M Yamamoto, J Osuga, Y Yazaki, S Yukawa, N Yamada: "A truncated species of apolipoprotein B (B-38.7) in a patient with homozygous hypobetalipoproteinemia associated with diabetes mellitus" Arterioscler Thromb Vasc Biol.18. 1330-1334

K Ohashi、S Ishibashi、M Yamamoto、J Osuga、Y Yazaki、S Yukawa、N Yamada：“与糖尿病相关的纯合性低β脂蛋白血症患者中载脂蛋白 B (B-38.7) 的截短种类”Arterioscler Thromb Vasc Biol.18

山田信博, 原田賢治 他: "Bcl-2 protein inhibits oxysterol-induced apoptosis through suppressing CPP32-mediated pathway." FEBS Lett. 411. 63-66 (1997)

Nobuhiro Yamada、Kenji Harada 等人：“Bcl-2 蛋白通过抑制 CPP32 介导的途径来抑制氧甾醇诱导的细胞凋亡。” FEBS Lett。