Transgenic study on the heterogeneity of intacellular triacylglycerol lipase

细胞内三酰甘油脂肪酶异质性的转基因研究

• 批准号: 11470232
• 负责人: ISHIBASHI Shun
• 金额: $ 9.54万
• 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: 1999
• 资助国家: 日本
• 起止时间: 1999 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-11470232/
• 关键词: Obesity; Adipocytes; Hormone-sensitive lipase; Triacylglycerol; Cholesterol; Infertility; Free fatty acids; catecholamoine; 糖尿病; リパーゼ; ジーンターゲティング; ノックアウトマウス

Obesity is frequently associated with various coronary risk factors such as diabetes, hyperlipidemia and hypertension. Obesity is primarily caused by excessive accumulation of triacylglycerol (TG) in adipocytes, and sometimes by the increased number of adipocytes. In particular, TG in the adipocytes is hydrolyzed by an enzyme, hormone-sensitive lipase (HSL), suggesting that HSL plays a important role in the development of obesity. However, no genetic abnormalities of HSL have been found to be associated with either clinical obesity or hyperlipidemia, prompting us to hypothesize that there are multiple TG lipases in adipocytes. Furthermore, it is known that HSL is widely expressed throughout the body, particularly in testis, adrenal glands, brain, cardiac muscle, skeletal muscle, pancreatic b-cells. However, the precise functions of HSL in these organs remain unclear. To clarify the role of HSL in obesity, we have generated HSL knockout mice.Exon 6 which encodes a central motif of the c … More atalytic site, GXSXG, has been replaced by neo cassette. Homologous recombination in ES cells produced mice lacking neutral cholesterol ester hydrolase (NCEH) activities in adipocytes and testes. HSL knockout mice exhibited male sterility due to oligospermia, Spermatogenesis may be disturbed in these mice. Even though NCEH activities were eliminated in adipocytes in both white adipose tissue (WAT) and brown adipose tissue (BAT), these adipocytes retained significant TG lipase activities which are distinct from HSL or from lipoprotein lipase (LPL). Body weight and weight of WAT were not increased in HSL knockout mice. However, individual adipocytes were enlarged by twice in diameter. These results suggest that there is heterogeneity in adipocyte populations in WAT.Consistent with the residual TG lipase activities in WAT, adipocytes isolated from WAT of HSL knockout mice showed an increase in FFA and glycerol release in response to isoprpterenol. From these results, we speculate that lipolysis is mediated by at least two distinct lipases, one is HSL and another is yet to be known. Less

肥胖通常与各种冠状动脉危险因素如糖尿病、高脂血症和高血压相关。肥胖主要是由脂肪细胞中三酰甘油（TG）的过度积累引起的，有时是由脂肪细胞数量增加引起的。特别是脂肪细胞中的TG被脂肪敏感脂肪酶（HSL）水解，表明HSL在肥胖的发展中起着重要作用。然而，没有发现HSL的遗传异常与临床肥胖或高脂血症相关，这促使我们假设脂肪细胞中存在多种TG脂肪酶。此外，已知HSL在整个身体中广泛表达，特别是在睾丸、肾上腺、脑、心肌、骨骼肌、胰腺b细胞中。然而，HSL在这些器官中的确切功能仍不清楚。为了阐明HSL在肥胖中的作用，我们建立了HSL基因敲除小鼠模型。 ...更多信息 催化位点GXSXG已被neo盒取代。ES细胞中的同源重组产生的小鼠在脂肪细胞和睾丸中缺乏中性胆固醇酯水解酶（NCEH）活性。HSL基因敲除小鼠由于少精子症而表现出雄性不育，这些小鼠的精子发生可能受到干扰。即使在白色脂肪组织（WAT）和棕色脂肪组织（BAT）的脂肪细胞中NCEH活性被消除，这些脂肪细胞仍保留显著的TG脂肪酶活性，这与HSL或脂蛋白脂肪酶（LPL）不同。HSL基因敲除小鼠的体重和WAT重量没有增加。然而，个别脂肪细胞的直径扩大了两倍。这些结果表明，有异质性的脂肪细胞群体在WAT。一致的残余TG脂肪酶活性在WAT，脂肪细胞分离的HSL基因敲除小鼠WAT表现出增加FFA和甘油释放响应异丙肾上腺素。从这些结果，我们推测，脂肪分解是介导的至少两个不同的脂肪酶，一个是HSL和另一个是尚未知道。少

项目成果

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Perrey S、Ishibashi S 等人：“噻唑烷二酮和肿瘤坏死因子 α 诱导分化的 3T3-L1 脂肪细胞中过氧化物酶体增殖物激活受体 γ mRNA 的下调。”代谢。

Yuan X, Ishibashi S, et al.: "The presence of telomeric G-strand tails in the telomerase catalytic subunit TERT knockout mice"Genes Cells. 4. 563-572 (1999)

Yuan X、Ishibashi S 等人：“端粒酶催化亚基 TERT 敲除小鼠中端粒 G 链尾部的存在”Genes Cells。

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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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Yahagi N，Ishibashi S，et al.：“sterpl调节元件结合蛋白-1在多不饱和脂肪酸调节脂肪生成基因表达中的关键作用”J.Biol.Chem.. 274. 35840-35844 (1999)

"Absence of ACAT-1 attenuates atherosclerosis but causesdry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia."J Biol Chem.. 275(28). 21324-30 (2000)

“ACAT-1 的缺失会减轻动脉粥样硬化，但会导致先天性高脂血症小鼠出现干眼症和皮肤黄瘤病。”J Biol Chem.. 275(28)。