Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells

• Published in: Disease models & mechanisms Vol. 7; no. 3; pp. 351 - 362
• Main Authors: Kong, Xiang Y, Nesset, Cecilie Kasi, Damme, Markus, Løberg, Else-Marit, Lübke, Torben, Mæhlen, Jan, Andersson, Kristin B, Lorenzo, Petra I, Roos, Norbert, Thoresen, G Hege, Rustan, Arild C, Kase, Eili T, Eskild, Winnie
• Format: Journal Article
• Language: English
• Published: England The Company of Biologists Ltd 01.03.2014; The Company of Biologists Limited; The Company of Biologists
• Subjects: Animals; Cathepsin D - metabolism; Cell Death; Collagen - metabolism; Female; Fertility; Fibrosis; Fluorescence; Gene expression; Gene Targeting; Genotype & phenotype; Growth factors; Hepatocytes - metabolism; Hepatocytes - pathology; Humans; Inflammation - pathology; Iron - metabolism; Kupffer Cells - metabolism; Kupffer Cells - pathology; Kupffer Cells - ultrastructure; Lipofuscin - metabolism; Liver; Liver - metabolism; Liver - pathology; Liver cirrhosis; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Lysosome; Lysosomes - metabolism; Male; Membrane Proteins - metabolism; Metabolism; Mice, Inbred C57BL; NCU-G1; Oxidative Stress; Phenotype; Proteins; Reproducibility of Results; Splenomegaly - metabolism; Splenomegaly - pathology; NCU-G1; Fibrosis; Lysosome
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.014050

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.