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Niemann-Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1  -/- mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA , a decrease of lipolytic gene expression, e.g., pparα and acox1 , and a decrease of lipid transporter gene expression, e.g., acat1 , abca1 and fatp2 . Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to pparα - and acox1- associated lipolysis/β-oxidation and to fatp2 -induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE . However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.

Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann–Pick-Disease Type C1