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1H NMR-Linked Metabolomics Analysis of Liver from a Mouse Model of NP-C1 Disease
journal contribution
posted on 2016-08-09, 00:00 authored by Victor Ruiz-Rodado, Elena-Raluca Nicoli, Fay Probert, David
A. Smith, Lauren Morris, Christopher A. Wassif, Frances M. Platt, Martin GrootveldClinical
manifestations of Niemann–Pick type C1 (NP-C1)
disease include neonatal hepatosplenomegaly and in some patients progressive
liver dysfunction and failure. This study involved a 1H
NMR-linked metabolomics analysis of liver samples collected from a
NP-C1 disease mutant mouse model in order to explore time-dependent
imbalances in metabolic pathways associated with NP-C1 liver dysfunction,
including fibrosis. NP-C1 mutant (Npc1–/–; NP-C1), control (Npc1+/+; WT), and
NP-C1 heterozygous mice (Npc1+/–; HET) were generated from heterozygote matings. Aqueous extracts
of these liver samples collected at time points of 3, 6, 9, and 11
weeks were subjected to high-resolution NMR analysis, and multivariate
(MV) metabolomics analyses of data sets acquired were performed. A
MV random forests (RFs) model effectively discriminated between NP-C1
and a combined WT/HET hepatic NMR profiles with very high predictive
accuracy and reliability. Key distinguishing features included significant
upregulations in the hepatic concentrations of phenylalanine, tyrosine,
glutamate, lysine/ornithine, valine, threonine, and hypotaurine/methionine,
and diminished levels of nicotinate/niacinamide, inosine, phosphoenolpyruvate,
and 3-hydroxyphenylacetate. Quantitative pathway topological analysis
confirmed that imbalances in tyrosine biosynthesis, and hepatic phenylalanine,
tyrosine, glutamate/glutamine, and nicotinate/niacinamide metabolism
were involved in the pathogenesis of NP-C1 disease-associated liver
dysfunction/damage. 1H NMR-linked metabolomics analysis
provides valuable biomarker information regarding hepatic dysfunction
or damage in NP-C1 disease.