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

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.
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
Journal	Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 3656 (03 06 2019) ISSN: 2045-2322 [Electronic] England
PMID	30842494 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Octopamine
Topics	Animals Chromosomes, Mammalian (genetics) Diet, High-Fat (adverse effects) Male Metabolomics (methods) Mice, Inbred BALB C Non-alcoholic Fatty Liver Disease (drug therapy, genetics, metabolism) Octopamine (administration & dosage, pharmacology) Polymorphism, Single Nucleotide Proton Magnetic Resonance Spectroscopy Quantitative Trait Loci Systems Biology Treatment Outcome

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.

Realize the full power of the drug-disease research graph!