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Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in Mice

Jelen, Sabina; Wacker, Soeren; Aponte-Santamaria, Camilo; Skott, Martin; Rojek, Aleksandra; Johanson, Urban LU ; Kjellbom, Per LU ; Nielsen, Soren; de Groot, Bert L. and Ruetzler, Michael (2011) In Journal of Biological Chemistry 286(52). p.44319-44325
Abstract
It has been hypothesized that aquaporin-9 (AQP9) is part of the unknown route of hepatocyte glycerol uptake. In a previous study, leptin receptor-deficient wild-type mice became diabetic and suffered from fasting hyperglycemia whereas isogenic AQP9(-/-) knock-out mice remained normoglycemic. The reason for this improvement in AQP9(-/-) mice was not established before. Here, we show increased glucose output (by 123% +/- 36% S. E.) in primary hepatocyte culture when 0.5 mM extracellular glycerol was added. This increase depended on AQP9 because it was absent in AQP9(-/-) cells. Likewise, the increase was abolished by 25 mu M HTS13286 (IC(50) similar to 2 mu M), a novel AQP9 inhibitor, which we identified in a small molecule library screen.... (More)
It has been hypothesized that aquaporin-9 (AQP9) is part of the unknown route of hepatocyte glycerol uptake. In a previous study, leptin receptor-deficient wild-type mice became diabetic and suffered from fasting hyperglycemia whereas isogenic AQP9(-/-) knock-out mice remained normoglycemic. The reason for this improvement in AQP9(-/-) mice was not established before. Here, we show increased glucose output (by 123% +/- 36% S. E.) in primary hepatocyte culture when 0.5 mM extracellular glycerol was added. This increase depended on AQP9 because it was absent in AQP9(-/-) cells. Likewise, the increase was abolished by 25 mu M HTS13286 (IC(50) similar to 2 mu M), a novel AQP9 inhibitor, which we identified in a small molecule library screen. Similarly, AQP9 deletion or chemical inhibition eliminated glycerol-enhanced glucose output in perfused liver preparations. The following control experiments suggested inhibitor specificity to AQP9: (i) HTS13286 affected solute permeability in cell lines expressing AQP9, but not in cell lines expressing AQPs 3, 7, or 8. (ii) HTS13286 did not influence lactate-and pyruvate-dependent hepatocyte glucose output. (iii) HTS13286 did not affect glycerol kinase activity. Our experiments establish AQP9 as the primary route of hepatocyte glycerol uptake for gluconeogenesis and thereby explain the previously observed, alleviated diabetes in leptin receptor-deficient AQP9(-/-) mice. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Biological Chemistry
volume
286
issue
52
pages
44319 - 44325
publisher
ASBMB
external identifiers
  • wos:000298645500003
  • scopus:84455173084
ISSN
1083-351X
DOI
10.1074/jbc.M111.297002
language
English
LU publication?
yes
id
92c0e204-d43e-4a2c-9462-6173b586fbab (old id 2303916)
date added to LUP
2012-01-31 11:18:25
date last changed
2017-08-27 03:03:24
@article{92c0e204-d43e-4a2c-9462-6173b586fbab,
  abstract     = {It has been hypothesized that aquaporin-9 (AQP9) is part of the unknown route of hepatocyte glycerol uptake. In a previous study, leptin receptor-deficient wild-type mice became diabetic and suffered from fasting hyperglycemia whereas isogenic AQP9(-/-) knock-out mice remained normoglycemic. The reason for this improvement in AQP9(-/-) mice was not established before. Here, we show increased glucose output (by 123% +/- 36% S. E.) in primary hepatocyte culture when 0.5 mM extracellular glycerol was added. This increase depended on AQP9 because it was absent in AQP9(-/-) cells. Likewise, the increase was abolished by 25 mu M HTS13286 (IC(50) similar to 2 mu M), a novel AQP9 inhibitor, which we identified in a small molecule library screen. Similarly, AQP9 deletion or chemical inhibition eliminated glycerol-enhanced glucose output in perfused liver preparations. The following control experiments suggested inhibitor specificity to AQP9: (i) HTS13286 affected solute permeability in cell lines expressing AQP9, but not in cell lines expressing AQPs 3, 7, or 8. (ii) HTS13286 did not influence lactate-and pyruvate-dependent hepatocyte glucose output. (iii) HTS13286 did not affect glycerol kinase activity. Our experiments establish AQP9 as the primary route of hepatocyte glycerol uptake for gluconeogenesis and thereby explain the previously observed, alleviated diabetes in leptin receptor-deficient AQP9(-/-) mice.},
  author       = {Jelen, Sabina and Wacker, Soeren and Aponte-Santamaria, Camilo and Skott, Martin and Rojek, Aleksandra and Johanson, Urban and Kjellbom, Per and Nielsen, Soren and de Groot, Bert L. and Ruetzler, Michael},
  issn         = {1083-351X},
  language     = {eng},
  number       = {52},
  pages        = {44319--44325},
  publisher    = {ASBMB},
  series       = {Journal of Biological Chemistry},
  title        = {Aquaporin-9 Protein Is the Primary Route of Hepatocyte Glycerol Uptake for Glycerol Gluconeogenesis in Mice},
  url          = {http://dx.doi.org/10.1074/jbc.M111.297002},
  volume       = {286},
  year         = {2011},
}