Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells
Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no det...
Main Authors: | , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
The Company of Biologists
2014-03-01
|
Series: | Disease Models & Mechanisms |
Subjects: | |
Online Access: | http://dmm.biologists.org/content/7/3/351 |
id |
doaj-118cd37476824946b0852ead9ad9bb7b |
---|---|
record_format |
Article |
spelling |
doaj-118cd37476824946b0852ead9ad9bb7b2020-11-25T01:12:34ZengThe Company of BiologistsDisease Models & Mechanisms1754-84031754-84112014-03-017335136210.1242/dmm.014050014050Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cellsXiang Y. KongCecilie Kasi NessetMarkus DammeElse-Marit LøbergTorben LübkeJan MæhlenKristin B. AnderssonPetra I. LorenzoNorbert RoosG. Hege ThoresenArild C. RustanEili T. KaseWinnie EskildHuman kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1gt/gt mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1gt/gt liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1gt/gt Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1gt/gt mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.http://dmm.biologists.org/content/7/3/351NCU-G1LysosomeFibrosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiang Y. Kong Cecilie Kasi Nesset Markus Damme Else-Marit Løberg Torben Lübke Jan Mæhlen Kristin B. Andersson Petra I. Lorenzo Norbert Roos G. Hege Thoresen Arild C. Rustan Eili T. Kase Winnie Eskild |
spellingShingle |
Xiang Y. Kong Cecilie Kasi Nesset Markus Damme Else-Marit Løberg Torben Lübke Jan Mæhlen Kristin B. Andersson Petra I. Lorenzo Norbert Roos G. Hege Thoresen Arild C. Rustan Eili T. Kase Winnie Eskild Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells Disease Models & Mechanisms NCU-G1 Lysosome Fibrosis |
author_facet |
Xiang Y. Kong Cecilie Kasi Nesset Markus Damme Else-Marit Løberg Torben Lübke Jan Mæhlen Kristin B. Andersson Petra I. Lorenzo Norbert Roos G. Hege Thoresen Arild C. Rustan Eili T. Kase Winnie Eskild |
author_sort |
Xiang Y. Kong |
title |
Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells |
title_short |
Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells |
title_full |
Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells |
title_fullStr |
Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells |
title_full_unstemmed |
Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells |
title_sort |
loss of lysosomal membrane protein ncu-g1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in kupffer cells |
publisher |
The Company of Biologists |
series |
Disease Models & Mechanisms |
issn |
1754-8403 1754-8411 |
publishDate |
2014-03-01 |
description |
Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1gt/gt mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1gt/gt liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1gt/gt Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1gt/gt mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage. |
topic |
NCU-G1 Lysosome Fibrosis |
url |
http://dmm.biologists.org/content/7/3/351 |
work_keys_str_mv |
AT xiangykong lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT ceciliekasinesset lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT markusdamme lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT elsemaritløberg lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT torbenlubke lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT janmæhlen lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT kristinbandersson lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT petrailorenzo lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT norbertroos lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT ghegethoresen lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT arildcrustan lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT eilitkase lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells AT winnieeskild lossoflysosomalmembraneproteinncug1inmiceresultsinspontaneousliverfibrosiswithaccumulationoflipofuscinandironinkupffercells |
_version_ |
1725165597124198400 |