Rojek Aleksandra M, Skowronski Mariusz T, Füchtbauer Ernst-Martin, Füchtbauer Annette C, Fenton Robert A, Agre Peter, Frøkiaer Jørgen, Nielsen Søren
The Water and Salt Research Center, University of Aarhus, DK-8000 Aarhus C, Denmark.
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3609-14. doi: 10.1073/pnas.0610894104. Epub 2007 Feb 21.
Aquaporin-9 (AQP9) is an aquaglyceroporin membrane channel shown biophysically to conduct water, glycerol, and other small solutes. Because the physiological role/s of AQP9 remain undefined and the expression sites of AQP9 remain incomplete and conflicting, we generated AQP9 knockout mice. In the absence of physiological stress, knockout mice did not display any visible behavioral or severe physical abnormalities. Immunohistochemical analyses using multiple antibodies revealed AQP9 specific labeling in hepatocytes, epididymis, vas deferens, and in epidermis of wild type mice, but a complete absence of labeling in AQP9(-/-) mice. In brain, no detectable labeling was observed. Compared with control mice, plasma levels of glycerol and triglycerides were markedly increased in AQP9(-/-) mice, whereas glucose, urea, free fatty acids, alkaline phosphatase, and cholesterol were not significantly different. Oral administration of glycerol to fasted mice resulted in an acute rise in blood glucose levels in both AQP9(-/-) and AQP9(+/-) mice, revealing no defect in utilization of exogenous glycerol as a gluconeogenic substrate and indicating a high gluconeogenic capacity in nonhepatic organs. Obese Lepr(db)/Lepr(db) AQP9(-/-) and obese Lepr(db)/Lepr(db) AQP9(+/-) mice showed similar body weight, whereas the glycerol levels in obese Lepr(db)/Lepr(db) AQP9(-/-) mice were dramatically increased. Consistent with a role of AQP9 in hepatic uptake of glycerol, blood glucose levels were significantly reduced in Lepr(db)/Lepr(db) AQP9(-/-) mice compared with Lepr(db)/Lepr(db) AQP9(+/-) in response to 3 h of fasting. Thus, AQP9 is important for hepatic glycerol metabolism and may play a role in glycerol and glucose metabolism in diabetes mellitus.
水通道蛋白9（AQP9）是一种水甘油通道蛋白膜通道，经生物物理学证明可传导水、甘油和其他小分子溶质。由于AQP9的生理作用仍不明确，且AQP9的表达位点仍不完整且存在矛盾，我们培育了AQP9基因敲除小鼠。在没有生理应激的情况下，基因敲除小鼠未表现出任何明显的行为或严重的身体异常。使用多种抗体进行的免疫组织化学分析显示，野生型小鼠的肝细胞、附睾、输精管和表皮中有AQP9特异性标记，但在AQP9（-/-）小鼠中完全没有标记。在大脑中，未观察到可检测到的标记。与对照小鼠相比，AQP9（-/-）小鼠的血浆甘油和甘油三酯水平显著升高，而葡萄糖、尿素、游离脂肪酸、碱性磷酸酶和胆固醇则无显著差异。给禁食小鼠口服甘油后，AQP9（-/-）和AQP9（+/-）小鼠的血糖水平均急性升高，这表明在将外源性甘油用作糖异生底物方面没有缺陷，并且表明非肝脏器官具有较高的糖异生能力。肥胖的Lepr（db）/Lepr（db）AQP9（-/-）和肥胖的Lepr（db）/Lepr（db）AQP9（+/-）小鼠体重相似，而肥胖的Lepr（db）/Lepr（db）AQP9（-/-）小鼠的甘油水平显著升高。与AQP9在肝脏摄取甘油中的作用一致，在禁食3小时后，Lepr（db）/Lepr（db）AQP9（-/-）小鼠的血糖水平与Lepr（db）/Lepr（db）AQP9（+/-）小鼠相比显著降低。因此，AQP9对肝脏甘油代谢很重要，可能在糖尿病的甘油和葡萄糖代谢中起作用。
