Abstract
Niemann-Pick type C (NPC) is a fatal autosomal recessive lysosomal storage disease clinically characterized by neurodegeneration and liver disease. Heterogeneous mutations in the NPC1 and NPC2 genes cause impaired egress of free cholesterol from lysosomes, leading to accumulation of cholesterol and glycosphingolipids. Key features of NPC liver disease include hepatic apoptosis, inflammation, and fibrosis. It is unclear what signaling events regulate these disease processes in NPC. We hypothesize that tumor necrosis factor alpha (TNF-alpha), which is involved in both proinflammatory and apoptotic signaling cascades, is a key mediator of inflammation, apoptosis, and fibrosis in NPC liver disease. In this study, we evaluated the role of TNF-alpha signaling in NPC liver disease by utilizing NPC1-specific antisense oligonucleotides to knock down NPC1 expression in control and TNF-alpha knockout mice. In the absence of TNF-alpha, NPC1 knockdown produced liver disease with significantly less inflammation, apoptosis, and fibrosis.
Highlights
Niemann-Pick type C (NPC) is a fatal autosomal recessive lysosomal storage disease clinically characterized by neurodegeneration and liver disease
NPC1 protein levels in the liver were completely ablated by NPC1 antisense oligonucleotide (ASO) treatment of C57BL/6 and TNF-a knockout mice (TNF KO) mice (Fig. 1A)
Knockdown of NPC1 in C56BL/6 mice led to hepatic accumulation of unesterified cholesterol and sphingosine
Summary
Niemann-Pick type C (NPC) is a fatal autosomal recessive lysosomal storage disease clinically characterized by neurodegeneration and liver disease. Key features of NPC liver disease include hepatic apoptosis, inflammation, and fibrosis. It is unclear what signaling events regulate these disease processes in NPC. We hypothesize that tumor necrosis factor a (TNF-a), which is involved in both proinflammatory and apoptotic signaling cascades, is a key mediator of inflammation, apoptosis, and fibrosis in NPC liver disease. TNF-a plays a role in hepatocyte apoptosis in Niemann-Pick type C liver disease. The multifunctional roles of TNF-a identify it as a potential key regulator of several aspects of NPC liver disease For these reasons, the goal of our study was to determine whether TNF-a plays a role in the pathogenesis of NPC liver disease. We conclude that in the absence of TNF-a, the progression of NPC liver disease is slowed, such that hepatocyte apoptosis, fibrosis, and foamy macrophage clustering are attenuated
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