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 detectable expression of this gene were created using a gene-trap strategy, and Ncu-g1(gt/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-g1(gt/gt) liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1(gt/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-g1(gt/gt) mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage.
Department of Bioscience, University of Oslo, 0316 Oslo, Norway.
Xiang Y
XY
Kong
Cecilie Kasi
CK
Nesset
Markus
M
Damme
Else-Marit
EM
Løberg
Torben
T
Lübke
Jan
J
Mæhlen
Kristin B
KB
Andersson
Petra I
PI
Lorenzo
Norbert
N
Roos
G Hege
GH
Thoresen
Arild C
AC
Rustan
Eili T
ET
Kase
Winnie
W
Eskild
D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D016923:Cell Death; D003094:Collagen / Q000378:metabolism; D005260:Female; D005453:Fluorescence; D018390:Gene Targeting; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007501:Iron / Q000378:metabolism*; D007728:Kupffer Cells / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008062:Lipofuscin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism* / Q000473:pathology; D008247:Lysosomes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D010641:Phenotype; D015203:Reproducibility of Results; D013163:Splenomegaly / Q000378:metabolism / Q000473:pathology
D008062:Lipofuscin; D008565:Membrane Proteins; C543310:NCU-G1 protein, mouse; D003094:Collagen; D007501:Iron; D002402:Cathepsin D
Fibrosis; Lysosome; NCU-G1