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

Abstract

Niemann-Pick type C (NP-C) disease is a fatal genetic lipidosis for which there is no Food and Drug Administration (FDA)-approved therapy. Vorinostat, an FDA-approved inhibitor of histone deacetylases, ameliorates lysosomal lipid accumulation in cultured NP-C patient fibroblasts. To assess the therapeutic potential of histone deacetylase inhibition, we pursued these observations in two murine models of NP-C disease. mice, which express a missense mutation in the gene, were treated intraperitoneally, from weaning, with the maximum tolerated dose of vorinostat (150 mg/kg, 5 days/week). Disease progression was measured via gene expression, liver function and pathology, serum and tissue lipid levels, body weight, and life span. Transcriptome analyses of treated livers indicated multiple changes consistent with reversal of liver dysfunction that typifies NP-C disease. Significant improvements in liver pathology and function were achieved by this treatment regimen; however, NPC1 protein maturation and levels, disease progression, weight loss, and animal morbidity were not detectably altered. Vorinostat concentrations were>200 μm in the plasma compartment of treated animals but were almost 100-fold lower in brain tissue. Apolipoprotein B metabolism and the expression of key components of lipid homeostasis in primary hepatocytes from null () and missense ( ) mutant mice were altered by vorinostat treatment, consistent with a response by these cells independent of the status of the locus. These results suggest that HDAC inhibitors have utility to treat visceral NP-C disease. However, it is clear that improved blood-brain barrier penetration will be required to alleviate the neurological symptoms of human NP-C disease.

Quantitative Analysis of the Proteome Response to the Histone Deacetylase Inhibitor (HDACi) Vorinostat in Niemann-Pick Type C1 disease

“…S5). These observations are consistent with the recent studies that Vorinostat alters liver APOB level in both Npc1 Ϫ/Ϫ and Npc1 nmf164 mouse model of NPC disease (55). In general, our data suggest that Vorinostat affects the differential expression of many lysosomal proteins in NPC1 I1061T fibroblasts, together which may contribute to the improvement in overall LE/Ly cholesterol homeostasis.…”

Animal models for Niemann-Pick type C: implications for drug discovery & development

“…Npc1 nmf164 presents with a similar phenotype but an overall less severe form of NPC than what is observed in Npc1 null mice, correlating with the partial loss of functional NPC1 protein [77]. The average lifespan is between 112 and 125 days in the C57BL/6 and BALB/c strains, respectively [49,78].…”

“…This mutation has not been described in human NPC patients, but the location in the large cysteine-rich luminal loop of the NPC1 protein makes it relevant to human disease as this is one of the mutational hotspots also accommodating the two most frequent pathological NPC1 mutations encoding the P1007A and I1061T missense mutations [1,75]. The D1005G mutation results in a misfolded and highly unstable mutant NPC1 protein that is prematurely degraded via ERAD [49,77].…”

“…The average lifespan is between 112 and 125 days in the C57BL/6 and BALB/c strains, respectively [49,78]. In addition to the progressive weight loss, Npc1 nmf164 mice display the characteristic lipid accumulation, hepatomegaly with accompanying decreased liver function and signs of injury, splenomegaly, brain involvement with cerebellar Purkinje cell loss, axonal abnormalities and increased astrocyte and microglial activation [49,77]. However, Npc1 nmf164 mice lack a profound demyelination phenotype (non-detectable by MRI), thus making this model unfit for analysis of this characteristic disease-associated parameter [49].…”

Correction of Niemann-Pick type C1 disease with the histone deacetylase inhibitor valproic acid

“…While HDACis have been shown to have positive effects on the folding, trafficking and function of NPC1 (18,60,128), they have also been linked to restoring WT-like expression profiles for lipid biosynthetic components, including enzymes involved in cholesterol biosynthesis (129)(130)(131), which are dysregulated in NPC1 disease (132). Most notably, SAHA has been shown to normalize the NPC-associated elevation in gene expression related to cholesterol biosynthesis, including the sterol regulatory element binding factor 2 (SREB2), a transcription factor that regulates cholesterol biosynthesis components, as well as the expression of Hmgcs1, Hmgcr, Mvk, Mvd, Idi1, Lss and Cyp51 (130). These data suggest that the therapeutic benefit of HDACis could be multifaceted, restoring balance to the dynamics of specialized compartments defining all steps of the endomembrane trafficking system.…”