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

• Main Authors: 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
• Format: Article
• Language: English
• Published: The Company of Biologists 2014-03-01
• Series: Disease Models & Mechanisms
• Subjects: NCU-G1; Lysosome; Fibrosis
• Online Access: http://dmm.biologists.org/content/7/3/351
• ISSN: 1754-8403; 1754-8411

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.