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

Abstract

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.

Main Olfactory and Vomeronasal Epithelium Are Differently Affected in Niemann-Pick Disease Type C1

“…However, plenty of data illustrate the beneficial effects of current symptomatic treatments. The combination of miglustat, HPβCD and allopregnanolone [ 27 , 28 , 32 , 33 , 58 ] leads to effective prevention of neurologic symptoms, and also reduced hepatopathology [ 6 , 59 ]. HPβCD seems to be the effective agent [ 9 , 34 ] by directly replacing the function of NPC proteins within endosomal and lysosomal compartments [ 60 , 61 ].…”

“…The reason is a mutation of the Npc1 gene on chromosome 18q11 that encodes a transmembranous transport protein with late endolysosomal localization [ 2 , 3 ] responsible for the release of cholesterol from lysosomes [ 4 ]. The resulting accumulation of cholesterol, however, is found predominantly in viscera like liver or spleen [ 5 , 6 , 7 , 8 , 9 ], whilst in cells of the nervous system, a different pathologic lipid pattern prevails, consisting of e.g., gangliosides GM2 and GM3 [ 5 , 10 ]. The range of symptoms reaches from hepatosplenomegaly and pulmonary ventilation disorders to neurologic/psychiatric symptoms such as ataxia, kataplexia, seisures, depression, progressive dementia, and retarded language development [ 11 , 12 , 13 ].…”

Gadolinium Chloride Rescues Niemann–Pick Type C Liver Damage

“…Alam et al (2016) obtained outstanding results, both in viscera and CNS, treating an NPC mouse model with the pan-HDAC inhibitor (HDACi) vorinostat, 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) [ 54 ]. Ebner et al (2018) tried a combination of HPβCD, miglustat, and allopregnanolone, obtaining a decrease in hepatic lipids and an amelioration of mouse NPC liver disease symptoms [ 55 ]. In this sense, gadolinium can be visualized as an alternative for a combination therapy along with other drugs such as cyclodextrin, capable of lowering the cholesterol burden, specifically directed to improve liver function in NPC disease.…”

Identification of Brain-Specific Treatment Effects in NPC1 Disease by Focusing on Cellular and Molecular Changes of Sphingosine-1-Phosphate Metabolism

“…Moreover, preliminary data of a multicenter, multinational phase 2b/3 clinical efficacy trial raised doubts concerning the benefit of the therapy [ 34 ]. With the aim of improving the therapeutic approach, a combination of miglustat, HPβCD and the neurosteroid allopregnanolone (pregnan-3alpha-ol-20-one) has been applied in animal models [ 12 , 30 , 35 , 36 , 37 ].…”

“…The BALB/cNctr-Npc1 m1N /J mouse model used in this study shows a neurological phenotype with neurovisceral lipid accumulation of cholesterol and sphingolipids [ 38 , 39 ]. Former studies using this NPC1 mouse model and the combination treatment with miglustat, HPβCD and allopregnanolone showed alleviated lipid storage in numerous organs (e.g., liver, spleen, olfactory epithelium, CNS), improved olfactory performance via increased regeneration of the olfactory epithelium, reduced cerebellar Purkinje-cell loss and decreased motor dysfunction [ 12 , 30 , 35 , 36 , 37 , 40 , 41 ]. Normally, the efflux of sphingolipids like sphingosine from the LE/LY is supported by the NPC1 protein [ 42 , 43 ].…”