Transgenic study on the heterogeneity of intacellular triacylglycerol lipase

肥胖经常与各种冠状动脉危险因素有关，如糖尿病、高脂血症和高血压。肥胖的主要原因是脂肪细胞中三酰甘油(TG)的过度积累，有时也是由于脂肪细胞数量的增加。特别是，脂肪细胞中的甘油三酯被激素敏感脂肪酶(HSL)降解，这表明HSL在肥胖的发生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有关，这促使我们假设脂肪细胞中存在多种甘油三酯脂肪酶。此外，众所周知，HSL广泛表达于全身，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，我们产生了hsl基因敲除小鼠。外显子6编码c…的一个中心基序。更混乱的GXSXG站点已经被NEO盒式磁带取代。ES细胞中的同源重组导致小鼠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为雄性不育，这些小鼠的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(BAT)中的脂肪细胞中的NCEH活性都被消除了，但这些脂肪细胞仍保留了明显的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，单个脂肪细胞的直径扩大了两倍。与WAT中残留的甘油三酯脂肪酶活性一致，HSL基因敲除小鼠WAT中分离的脂肪细胞对异丙肾上腺素的反应增加了游离脂肪酸和甘油的释放。根据这些结果，我们推测脂肪分解至少由两种不同的脂肪酶介导，一种是HSL，另一种尚不清楚。较少

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we have generated HSL knockout mice.Exon 6 which encodes a central motif of the c … More atalytic site, GXSXG, has been replaced by neo cassette.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