Clarification of the physiological mechanism in a novel adipose specific glycerol channel discovered by us

水通道蛋白脂肪(AQPap)是一种脂肪专一性的甘油通道。我们在小鼠AQPap基因启动子区域发现了PPRE激活的受体。在体内和组织培养中，AQPap基因的表达受胰岛素的负调控，PPARγγ与该元件的结合和激活解释了AQPap基因的脂肪特异性表达。在对AQPap启动子的分析中，我们发现了一个由7个核苷酸组成的胰岛素负反应元件；在对160名受试者的AQPap基因突变的研究中，我们发现了3种不同类型的错义突变(R12C、V59L、G264V)和两种类型的沉默突变(A103A、G250G)。通过功能分析，G264V型AQPap不能利用非洲爪哇卵母细胞系统转运甘油。AQPap纯合子Far G264V AQPap未能在剧烈运动后引起血浆甘油浓度升高，而血浆去甲肾上腺素水平与之相当，提示AQPap在人体内通过运动介导脂肪组织中甘油的释放。我们正在研究AQPap基因敲除小鼠的表型，以阐明AQPap和全身甘油代谢的生理意义。

Aquaporin adipose (AQPap) is an adipose-specific glycerol channel. We identified the peroxisome proliferator response element (PPRE) activated receptor in the promoter region of mouse AQPap gene. Binding and activation of peroxisome proliferator activated receptor γ (PPARγ) to this element was suggested to explain the adipose-specific expression of AQPap mRNA.AQPap gene expression was negatively regulated by insulin in vivo and in tissue cultures. In the analysis of AQPap promoter, we showed there was an insulin negative response element composed of seven nucleotides.In the search of genetic mutations of AQPap in 160 human subjects, we found three different types of missense mutation (R12C, V59L, G264V) and two types of silent mutations (A103A, G250G). By the functional analysis, the G264V-type AQPap was not capable of transporting glycerol using the xenopus oocyte system. The homozygous subject far G264V AQPap failed to raise the concentrations of plasma glycerol in response to vigorous exercise, while there was an equivalent serge of plasma noradrenalin, suggesting that the AQPap is mediating the glycerol release from adipose tissues by exercise in human.We are now investigating the phenotypes of AQPap knockout mice to clarify the physiological significance of AQPap and glycerol metabolism in whole body.