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]
ursodeoxycholic acid (UDCA) treatment had no impact on the histopathology of wild type and Npc1-/- mice, whereas cholic acid (CA) treatment led to hepatocyte enlargement and a foamy appearance indicative of lipid accumulation that often displaced the nucleus to the pole of the cell
The bile acid profile is altered in NPC disease[4,5], and this change in bile acid composition leads to a secondary suppression of the P450 gene family, as they are bile acid regulated[3]
Summary
Niemann-Pick disease type C (NPC) is a rare progressive neurodegenerative lysosomal disorder, which affects 1:100,000 live births[1,2]. 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[4,5], which suppresses gene expression of the P450 system[3]. Treatment of Npc1-/- mice with ursodeoxycholic acid (UDCA; 3α, 7β-dihydroxy-5β-cholanic acid) rescued gene expression and P450 system enzyme activity[3]. 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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