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Systems Genetics of Hepatic Metabolome Reveals Octopamine as a Target for Non-Alcoholic Fatty Liver Disease Treatment

Lookup NU author(s): Professor Chris Day, Professor Alastair Burt

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2019, The Author(s). Non-alcoholic fatty liver disease (NAFLD) is often associated with obesity and type 2 diabetes. To disentangle etiological relationships between these conditions and identify genetically-determined metabolites involved in NAFLD processes, we mapped 1 H nuclear magnetic resonance (NMR) metabolomic and disease-related phenotypes in a mouse F2 cross derived from strains showing resistance (BALB/c) and increased susceptibility (129S6) to these diseases. Quantitative trait locus (QTL) analysis based on single nucleotide polymorphism (SNP) genotypes identified diet responsive QTLs in F2 mice fed control or high fat diet (HFD). In HFD fed F2 mice we mapped on chromosome 18 a QTL regulating liver micro- and macrovesicular steatosis and inflammation, independently from glucose intolerance and adiposity, which was linked to chromosome 4. Linkage analysis of liver metabolomic profiling data identified a QTL for octopamine, which co-localised with the QTL for liver histopathology in the cross. Functional relationship between these two QTLs was validated in vivo in mice chronically treated with octopamine, which exhibited reduction in liver histopathology and metabolic benefits, underlining its role as a mechanistic biomarker of fatty liver with potential therapeutic applications.


Publication metadata

Author(s): Brial F, Le Lay A, Hedjazi L, Tsang T, Fearnside JF, Otto GW, Alzaid F, Wilder SP, Venteclef N, Cazier J-B, Nicholson JK, Day C, Burt AD, Gut IG, Lathrop M, Dumas M-E, Gauguier D

Publication type: Article

Publication status: Published

Journal: Scientific Reports

Year: 2019

Volume: 9

Issue: 1

Online publication date: 06/03/2019

Acceptance date: 17/01/2019

Date deposited: 20/03/2019

ISSN (electronic): 2045-2322

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41598-019-40153-0

DOI: 10.1038/s41598-019-40153-0

PubMed id: 30842494


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