Abstract
BackgroundNiemann-Pick type C disease (NPC) is a neurovisceral lipid storage disorder mainly characterized by unesterified cholesterol accumulation in lysosomal/late endosomal compartments, although there is also an important storage for several other kind of lipids. The main tissues affected by the disease are the liver and the cerebellum. Oxidative stress has been described in various NPC cells and tissues, such as liver and cerebellum. Although considerable alterations occur in the liver, the pathological mechanisms involved in hepatocyte damage and death have not been clearly defined. Here, we assessed hepatic tissue integrity, biochemical and oxidative stress parameters of wild-type control (Npc1 +/+; WT) and homozygous-mutant (Npc1 −/−; NPC) mice. In addition, the mRNA abundance of genes encoding proteins associated with oxidative stress, copper metabolism, fibrosis, inflammation and cholesterol metabolism were analyzed in livers and cerebella of WT and NPC mice.Methodology/Principal FindingsWe analyzed various oxidative stress parameters in the liver and hepatic and cerebellum gene expression in 7-week-old NPC1-deficient mice compared with control animals. We found signs of inflammation and fibrosis in NPC livers upon histological examination. These signs were correlated with increased levels of carbonylated proteins, diminished total glutathione content and significantly increased total copper levels in liver tissue. Finally, we analyzed liver and cerebellum gene expression patterns by qPCR and microarray assays. We found a correlation between fibrotic tissue and differential expression of hepatic as well as cerebellar genes associated with oxidative stress, fibrosis and inflammation in NPC mice.Conclusions/SignificanceIn NPC mice, liver disease is characterized by an increase in fibrosis and in markers associated with oxidative stress. NPC is also correlated with altered gene expression, mainly of genes involved in oxidative stress and fibrosis. These findings correlate with similar parameters in cerebellum, as has been previously reported in the NPC mice model.
Highlights
Niemann-Pick type C disease (NPC) is a neurovisceral atypical lipid storage disorder involving endocytosed cholesterol [1], as well as other kind of lipids
Protein carbonyls were significantly increased (Figure 2A), while glutathione showed a tendency to decrease (Figure 2B) in livers of NPC mice compared to WT mice. These results suggest that the histological changes observed in NPC mice are correlated with oxidative stress
We found an upregulation of several genes related with cholesterol metabolism (Cd36, lipoprotein lipase (Lpl), fatty acid binding protein 4 (Fabp4) and Ncp2; orange bars) but in only one involved with inflammation and fibrosis (Vim; red bar)
Summary
Niemann-Pick type C disease (NPC) is a neurovisceral atypical lipid storage disorder involving endocytosed cholesterol [1], as well as other kind of lipids. The disease is often diagnosed in early childhood, with patients typically displaying cerebellar ataxia, difficulty speaking and swallowing, and progressive dementia [1,3] These symptoms are associated with damage to the central nervous system (CNS), especially in the cerebellum, where extensive and progressive neuronal death is observed [8]. Niemann-Pick type C disease (NPC) is a neurovisceral lipid storage disorder mainly characterized by unesterified cholesterol accumulation in lysosomal/late endosomal compartments, there is an important storage for several other kind of lipids. The mRNA abundance of genes encoding proteins associated with oxidative stress, copper metabolism, fibrosis, inflammation and cholesterol metabolism were analyzed in livers and cerebella of WT and NPC mice
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