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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-12

AUTHORS

Francois Brial, Aurélie Le Lay, Lyamine Hedjazi, Tsz Tsang, Jane F. Fearnside, Georg W. Otto, Fawaz Alzaid, Steven P. Wilder, Nicolas Venteclef, Jean-Baptiste Cazier, Jeremy K. Nicholson, Chris Day, Alastair D. Burt, Ivo G. Gut, Mark Lathrop, Marc-Emmanuel Dumas, Dominique Gauguier

ABSTRACT

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 1H 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. More... »

PAGES

3656

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41598-019-40153-0

DOI

http://dx.doi.org/10.1038/s41598-019-40153-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1112567318

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30842494


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