TNF-α plays a role in hepatocyte apoptosis in Niemann-Pick type C liver disease

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 a (TNF-α), 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-α signaling in NPC liver disease by utilizing NPC1-specific antisense oligonucleotides to knock down NPC1 expression in control and TNF-a knockout mice. In the absence of TNF-α, NPC1 knockdown produced liver disease with significantly less inflammation, apoptosis, and fibrosis. Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc.