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<div> <div> <strong><em>Physiology</em></strong> </div> <div> </div> <h2>Aquaglyceroporin AQP9: Solute permeation and metabolic control of expression in liver</h2> <div> <strong> </strong> </div> <div> <strong>Jennifer M. Carbrey, Daniel A. Gorelick-Feldman, David Kozono, Jeppe Praetorius, Søren Nielsen, </strong>and<strong> Peter Agre</strong> <div> </div> <div> <em>Departments of <sup>*</sup>Biological Chemistry and <sup>§</sup>Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205; and <sup>‡</sup>Water and Salt Research Center, University of Aarhus, DK-8000 Aarhus, Denmark</em> </div> </div> </div> <div> </div> <h3>Abstract</h3> <div style="text-transform:uppercase;"> <strong></strong> </div> <div> Aquaglyceroporins form the subset of the aquaporin water channel family that is permeable to glycerol and certain small, uncharged solutes. AQP9 has unusually broad solute permeability and is expressed in hepatocyte plasma membranes. Proteoliposomes reconstituted with expressed, purified rat AQP9 protein were compared with simple liposomes for solute permeability. At pH 7.5, AQP9 proteoliposomes exhibited Hg<sup>2+</sup>-inhibitible glycerol and urea permeabilities that were increased 63-fold and 90-fold over background. β-Hydroxybutyrate permeability was not increased above background, and osmotic water permeability was only minimally elevated. During starvation, the liver takes up glycerol for gluconeogenesis. Expression of AQP9 in liver was induced up to 20-fold in rats fasted for 24–96 h, and the AQP9 level gradually declined after refeeding. No changes in liver AQP9 levels were observed in rats fed ketogenic diets or high-protein diets, but AQP9 levels were elevated in livers of rats made diabetic by streptozotocin injection. When blood glucose levels of the diabetic rats were restored to normal by insulin treatments, the AQP9 levels returned to baseline. Confocal immunofluorescence revealed AQP9 immunostaining on the sinusoidal surfaces of hepatocyte plates throughout the livers of control rats. Denser immunostaining was observed in the same distribution in livers of fasted and streptozotocin-treated rats. We conclude that AQP9 serves as membrane channel in hepatocytes for glycerol and urea at physiological pH, but not for β-hydroxybutyrate. In addition, levels of AQP9 expression fluctuate depending on the nutritional status of the subject and the circulating insulin levels. </div> <div> </div> <div> <em>Proc Natl Acad Sci U S A. 2003 March 4; 100(5): 2945–2950. © 2003, The National Academy of Sciences.</em> </div> <div> <em></em> </div> <div> </div> <div> </div> <div> <hr></div> <div> </div> <div> <em></em> </div> <div> <em></em> </div> <div> The AQP9 cDNA was first isolated during efforts to clone urea transporters by expression in oocytes (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B1">1</a>). Expressed in testes, leukocytes, and brain, AQP9 is abundant in liver (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B1">1</a>) where it resides in hepatocyte plasma membranes facing the sinusoids (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B2">2</a>–<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B4">4</a>). The coding sequence of AQP9 is more closely related to AQP3 (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B5">5</a>) and AQP7 (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B6">6</a>), which are both permeated by glycerol and water. This subset of proteins, referred to as aquaglyceroporins, is functionally distinct from the water-selective homologs AQP1, AQP2, AQP4, and AQP5 (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B7">7</a>). The original studies of <em>Xenopus laevis</em> oocytes expressing rat AQP9 reported permeability to a wide range of <sup>14</sup>C- or <sup>3</sup>H-labeled solutes including polyols, carbamides, purines, pyrimidines, nucleosides, and monocarboxylates (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B1">1</a>). Glycerol and urea permeability have been confirmed with AQP9 oocytes (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B8">8</a>), but studies of proteoliposomes reconstituted with purified AQP9 protein have not been reported. <p> The physiological functions of AQP9 are uncertain. During prolonged fasting, glycerol released from adipocytes via AQP7 may be taken up by the liver via AQP9 for gluconeogenesis. Urea, a byproduct of amino acid deamination, and β-hydroxybutyrate, an alternative fuel, may be released from liver via AQP9. An elegant series of recent studies of adipocyte AQP7 and liver AQP9 mRNAs and promoters suggested that the genes are coordinately regulated during fasting and type 1 diabetes mellitus (<a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12594337#B9">9</a>), but this has not been confirmed with studies of the AQP7 and AQP9 proteins. </p> <p> We undertook studies to define the permeation of proteoliposomes reconstituted with purified rat AQP9 protein and to provide evidence that expression of AQP9 protein is altered in rats during fasting and insulin deficiency. Our studies indicate that AQP9 facilitates hepatocyte glycerol influx and urea efflux, establishing a greater functional repertoire for AQP9 as a solute channel with minor water transport capacity. </p> </div>
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