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 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.

• Authors: Victor Ruiz-Rodado, Elena-Raluca Nicoli, Fay Probert, David A Smith, Lauren Morris, Christopher A Wassif, Frances M Platt, Martin Grootveld
• Journal: Journal of proteome research (J Proteome Res) Vol. 15 Issue 10 Pg. 3511-3527 (10 07 2016) ISSN: 1535-3907 [Electronic] United States
• PMID: 27503774 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers

Topics

• Animals
• Biomarkers
• Disease Models, Animal
• Liver (metabolism)
• Liver Diseases
• Magnetic Resonance Spectroscopy
• Metabolic Networks and Pathways
• Metabolomics
• Mice
• Niemann-Pick Disease, Type C (metabolism)
• Time Factors