Abstract
BackgroundMice lacking glycosylated lysosomal membrane protein (Glmpgt/gt mice) have liver fibrosis as the predominant phenotype due to chronic liver injury. The Glmpgt/gt mice grow and reproduce at the same rate as their wild-type siblings. Life expectancy is around 18 months.MethodsWild-type and Glmpgt/gt mice were studied between 1 week and 18 months of age. Livers were analyzed using histological, immunohistochemical, biochemical, and qPCR analyses.ResultsIt was shown that Glmpgt/gt mice were not born with liver injury; however, it appeared shortly after birth as indicated by excess collagen expression, deposition of fibrous collagen in the periportal areas, and increased levels of hydroxyproline in Glmpgt/gt liver. Liver functional tests indicated a chronic, mild liver injury. Markers of inflammation, fibrosis, apoptosis, and modulation of extracellular matrix increased from an early age, peaking around 4 months of age and followed by attenuation of these signals. To compensate for loss of hepatocytes, the oval cell compartment was activated, with the highest activity of the oval cells detected at 3 months of age, suggesting insufficient hepatocyte proliferation in Glmpgt/gt mice around this age. Although constant proliferation of hepatocytes and oval cells maintained adequate hepatic function in Glmpgt/gt mice, it also resulted in a higher frequency of liver tumors in older animals.ConclusionsThe Glmpgt/gt mouse is proposed as a model for slowly progressing liver fibrosis and possibly as a model for a yet undescribed human lysosomal disorder.Electronic supplementary materialThe online version of this article (doi:10.1186/s13069-016-0042-4) contains supplementary material, which is available to authorized users.
Highlights
Mice lacking glycosylated lysosomal membrane protein (Glmpgt/gt mice) have liver fibrosis as the predominant phenotype due to chronic liver injury
We recently reported the successful generation of a mouse model lacking expression of the glycosylated lysosomal membrane protein (GLMP) [28]
Chronic liver inflammation is initiated shortly after birth in Glmpgt/gt mice As a background for evaluating the lack of GLMP expression on liver health, we measured the messenger RNA (mRNA) levels for Glmp from birth till 9 months of age
Summary
Mice lacking glycosylated lysosomal membrane protein (Glmpgt/gt mice) have liver fibrosis as the predominant phenotype due to chronic liver injury. A heterogeneous group of more than 50 congenital metabolic disorders characterized by the lack or dysfunction of a protein within the endo-lysosomal pathway has been described and categorized as lysosomal disorders [4,5,6,7,8,9,10,11] Most of these proteins are degradative enzymes or membrane proteins [10, 11]. These lysosomal disorders have widely varying phenotypes; symptoms are often observed in tissues with low proliferation capacity, such as the brain, or in cell types with a high substrate turnover such as hepatocytes [7, 8, 12, 13].
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