Brial, FrancoisLe Lay, AurélieHedjazi, LyamineTsang, TszFearnside, Jane F.Otto, Georg W.Alzaid, FawazWilder, Steven P.Venteclef, NicolasCazier, Jean-BaptisteNicholson, Jeremy K.Day, ChrisBurt, Alastair D.Gut, Ivo GlynneLathrop, MarkDumas, Marc-EmmanuelGauguier, Dominique2019-05-212019-05-212019Brial F, Le Lay A, Hedjazi L, Tsang T, Fearnside JF, Otto GW, Alzaid F, Wilder SP, Venteclef N, Cazier JB, Nicholson JK, Day C, Burt AD, Gut IG, Lathrop M, Dumas ME, Gauguier D. Systems genetics of hepatic metabolome reveals octopamine as a target for non-alcoholic fatty liver disease treatment. Sci Rep. 2019; 9(1):3656. DOI 10.1038/s41598-019-40153-02045-2322http://hdl.handle.net/10230/37251Non-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.application/pdfeng© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s41598-019-40153-0Genetic linkage studyNutrigenomicsinfo:eu-repo/semantics/openAccess