Abstract
Niemann-Pick disease type C (NPC) disease is a neurodegenerative lysosomal storage disease caused by mutations in the NPC1 or NPC2 genes. Liver disease is also a common feature of NPC that can present as cholestatic jaundice in the neonatal period. Liver enzymes can remain elevated above the normal range in some patients as they age. We recently reported suppression of the P450 detoxification system in a mouse model of NPC disease and in post-mortem liver from NPC patients. As bile acids regulate the P450 system, we tested bile acid treatment using ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid), a hydrophilic bile acid, which is used to treat several cholestatic disorders. In this study, we compared UDCA treatment with the bile acid cholic acid (CA), and found unexpected hepatotoxicity in response to CA in Npc1 mice, but not to UDCA, suggesting that only UDCA should be used as an adjunctive therapy in NPC patients.
Highlights
Niemann-Pick disease type C (NPC) is a rare progressive neurodegenerative lysosomal disorder, which affects 1:100,000 live births[1,2]
We investigated the effects of ursodeoxycholic acid (UDCA) and cholic acid (CA) treatment in the Npc1-/- mouse model, relative to wild type (Npc1+/+) mice
After 3 weeks of treatment there was gross abdominal distention observed in all CA treated mice, irrespective of genotype, but the degree of distension appeared greater in the Npc1-/- mice
Summary
Niemann-Pick disease type C (NPC) is a rare progressive neurodegenerative lysosomal disorder, which affects 1:100,000 live births[1,2]. Previous published studies of murine Npc1-/- models identified other treatment modalities for hepatic dysfunction. These included the cholesterol absorption inhibitor, ezetimibe, and 2-hydroxypropyl-β-cyclodextrin (2HPβCD)[3]. We recently discovered that the hepatic cytochrome P450 system is suppressed in the Npc[1] null mouse model (Npc1-/-), in the feline model of NPC disease and in three NPC human liver samples (post-mortem)[4]. In NPC, the efflux of unesterified cholesterol from late endosomes/lysosomes to the endoplasmic reticulum (ER) is inhibited, leading to a shift in the spectrum of bile acids synthesized[5,6], which suppresses gene expression of the P450 system[4]. We compared the effects of UDCA (soluble bile acid) and cholic acid (CA; hydrophobic bile acid) in the Npc1-/- mouse and discovered hepatotoxic adverse effects on the liver in response to CA, but not to UDCA, suggesting UDCA is the bile acid of choice for clinical treatment of NPC patients
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