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

基本信息

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

项目摘要

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we have generated HSL knockout mice.Exon 6 which encodes a central motif of the c … More atalytic site, GXSXG, has been replaced by neo cassette.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

肥胖常常与多种冠状动脉危险因素有关，例如糖尿病、高脂血症和高血压。肥胖主要是由于脂肪细胞中三酰甘油(TG)的过度积累，有时是由于脂肪细胞中的TG被水解所致。激素敏感性脂肪酶 (HSL) 的作用，表明 HSL 在肥胖的发生中发挥着重要作用，然而，尚未发现 HSL 的遗传异常与这两者相关。临床肥胖或高脂血症，促使我们认为脂肪细胞中存在多种TG脂肪酶。此外，已知HSL在全身广泛表达，特别是在睾丸、肾上腺、大脑、心肌、骨骼肌、胰腺b-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，我们培育了 HSL 敲除小鼠。外显子 6 编码 c 的中心基序。 …更多催化位点 GXSXG 已被 Neo 盒取代，在脂肪细胞和睾丸中缺乏中性胆固醇酯水解酶 (NCEH) 活性的小鼠中，HSL 敲除小鼠表现出雄性不育，精子发生可能受到干扰。尽管白色脂肪组织 (WAT) 和棕色脂肪组织的脂肪细胞中 NCEH 活性均被消除。 (BAT)，这些脂肪细胞保留了与 HSL 或脂蛋白脂肪酶 (LPL) 不同的显着的 TG 脂肪酶活性，HSL 敲除小鼠的体重和 WAT 重量没有增加，但单个脂肪细胞的直径增大了两倍。表明 WAT 中的脂肪细胞群存在异质性。与 WAT 中残留的 TG 脂肪酶活性一致，从 HSL 敲除小鼠的 WAT 中分离的脂肪细胞显示 FFA 增加，根据这些结果，我们推测脂肪分解是由至少两种不同的脂肪酶介导的，一种是 HSL，另一种尚不清楚。