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

2014, Disease Models & Mechanisms

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. . Myeloperoxidase and elastase are only expressed by neutrophils in normal and in inflamed liver. Histochem. Cell Biol. 135, 305-315. Barrett, A. J. (1980). Fluorimetric assays for cathepsin B and cathepsin H with methylcoumarylamide substrates. Biochem. J. 187, 909-912. . Transcriptional profiling reveals novel markers of liver fibrogenesis: gremlin and insulin-like growth factor-binding proteins. . (2003b). Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis. J. Clin. Invest. 112, 152-159. . Cholesteryl ester storage disease: pathologic changes in an affected fetus. Am. J. Med. Genet. 26, 689-698. Engelhardt, N. V., Factor, V. M., Yasova, A. K., Poltoranina, V. S., Baranov, V. N. and Lasareva, M. N. (1990). Common antigens of mouse oval and biliary epithelial cells. Expression on newly formed hepatocytes. Differentiation 45, 29-37. Engelhardt, N. V., Factor, V. M., Medvinsky, A. L., Baranov, V. N., Lazareva, M. N. and Poltoranina, V. S. (1993). Common antigen of oval and biliary epithelial cells (A6) is a differentiation marker of epithelial and erythroid cell lineages in early development of the mouse. Differentiation 55, 19-26.