Recovery from liver disease in a Niemann-Pick type C mouse model

Abstract

This article is available online at http://www.jlr.org clinical cases and NPC2 in 5% of clinical cases. NPC is characterized by storage of free cholesterol and glycosphingolipids in late endosomes and lysosomes. The clinical phenotype that arises, neurodegeneration, hepatosplenomegaly, ataxia, seizures, and dystonia, is similar regardless of whether NPC1 or NPC2 is the cause ( 1 ).Although most NPC patients die due to complications of their neurodegenerative disease, some patients also develop liver disease. Aside from hepatosplenomegaly, NPC patients often suffer from prolonged neonatal jaundice and ascites ( 2 ), as well as liver failure ( 3-7 ). NPC is the second most common cause of neonatal cholestasis ( 7 ), and 10% of these patients die because of liver failure ( 8 ). On the tissue level, livers from NPC-diseased mice exhibit increased hepatocyte apoptosis, infi ltration of foamy macrophages, infl ammation, proliferation of hepatic stellate cells, and fi brosis ( 9-11 ). To better understand liver disease in NPC, our laboratory has developed a mouse model using 2'-O -methoxyethyl modifi ed antisense oligonucleotides (ASO) to block expression of NPC1 specifi cally in the liver ( 10 ).In the present study, we aimed to determine whether recovery is possible in mice with NPC-associated liver disease by using ASOs to knock down hepatic NPC1 expression. After halting treatment for different lengths of time, liver disease was assessed. We hypothesized that extensive liver recovery was possible in NPC1 ASO-treated mice, because the liver has a remarkable capacity for regeneration ( 12 ). Here, we show that substantial reversal of the NPC disease phenotype occurred, including alleviation of hepatomegaly, loss of lipid-laden macrophage accumulations, and decreasing liver cell apoptosis. Much pathology Abstract Loss of function of Niemann-Pick C1 (NPC1) leads to lysosomal free cholesterol storage, resulting in the neurodegenerative disease Niemann-Pick disease type C (NPC). Signifi cant numbers of patients with NPC also suffer from liver disease. Currently, no treatments exist that alter patient outcome, and it is unknown if recovery from tissue damage can occur even if a treatment were found. Our laboratory developed a strategy to test whether mice can recover from NPC liver disease. We used antisense oligonucleotides to knock down hepatic expression of NPC1 in BALB/C mice for either 9 or 15 weeks. This recapitulated liver disease with hepatomegaly, cell death, and fi brosis. Then, antisense oligonucleotide treatment was halted for an additional 4, 9, or 15 weeks. We report that significant liver recovery occurred even when NPC1 protein expression only partially returned to normal. Several pathological phenotypes were alleviated, including hepatomegaly, cholesterol storage, and liver cell death. Histological examination revealed that foamy cell accumulation was relieved; however, liver fi brosis increased. Additionally, resolution of cholesterol storage and liver cell death took longer in mice with long-term knockd...

Normalization of Hepatic Homeostasis in the Npc1 Mouse Model of Niemann-Pick Type C Disease Treated with the Histone Deacetylase Inhibitor Vorinostat

“…Vorinostat Improves Liver Health-To determine whether the transcriptional regulation of cholesterol metabolism by vorinostat has functional consequences, we measured serum levels of alanine aminotransferase (ALT), an enzyme that is elevated in NP-C disease as a consequence of liver damage (39). Serum ALT levels were significantly higher (73.9%) in the PEG/ DMSO-treated Npc1 nmf164 mice compared with PEG/DMSOtreated control mice.…”

Niemann-Pick C disease and mobilization of lysosomal cholesterol by cyclodextrin

“…These impairments contribute to the reduced weight gain, cognitive decline, and premature death that characterize NPC disease. Severe liver disease is also prevalent in many NPC-defi cient patients ( 2 ) and mice (53)(54)(55)(56). The majority ( ‫ف‬ 80%) of circulating LDLs are cleared by the liver via receptor-mediated endocytosis ( 57,58 ).…”

Plasma Signature of Neurological Disease in the Monogenetic Disorder Niemann-Pick Type C

“…At the cellular level, there is prominent accumulation of foamy macrophages in liver (9,10,13) and activation of microglia in brain (14). Impaired development and reduced natural killer T cells in spleen and thymus have been found in NPC null mice (15,16).…”