title: 1H NMR-Linked Metabolomics Analysis of Liver from a Mouse Model of NP-C1 Disease.
abstract: Clinical manifestations of Niemann-Pick type C1 (NP-C1) disease include neonatal hepatosplenomegaly and in some patients progressive liver dysfunction and failure. This study involved a1H 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.
authors: Leicester School of Pharmacy, De Montfort University , The Gateway, Leicester LE1 9BH, United Kingdom.
authors: Victor
authors: V
authors: Ruiz-Rodado
authors: Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors: Elena-Raluca
authors: ER
authors: Nicoli
authors: Leicester School of Pharmacy, De Montfort University , The Gateway, Leicester LE1 9BH, United Kingdom.
authors: Fay
authors: F
authors: Probert
authors: Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors: David A
authors: DA
authors: Smith
authors: Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors: Lauren
authors: L
authors: Morris
authors: Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom.|Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH , Bethesda, Maryland 20892, United States.
authors: Christopher A
authors: CA
authors: Wassif
authors: Department of Pharmacology, University of Oxford , Mansfield Road, Oxford OX1 3QT, United Kingdom.
authors: Frances M
authors: FM
authors: Platt
authors: Leicester School of Pharmacy, De Montfort University , The Gateway, Leicester LE1 9BH, United Kingdom.
authors: Martin
authors: M
authors: Grootveld
mesh_terms: D000818:Animals; D015415:Biomarkers; D004195:Disease Models, Animal; D008099:Liver / Q000378:metabolism*; D008107:Liver Diseases; D009682:Magnetic Resonance Spectroscopy; D053858:Metabolic Networks and Pathways; D055432:Metabolomics; D051379:Mice; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015415:Biomarkers
keywords: 3-hydroxyphenylacetate; NMR-based metabolomics; NP-C1 disease; amino acid biosynthesis and metabolism; biomarkers; fibrosis−cirrhosis; liver damage/dysfunction; metabolic pathway analysis; nicotinate and niacinamide metabolism