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Sci Rep. 2019 Mar 6;9(1):3656. doi: 10.1038/s41598-019-40153-0.

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

Author information

1
Sorbonne University, University Paris Descartes, University Paris Diderot, INSERM UMR_S 1138, Cordeliers Research Centre, 75006, Paris, France.
2
Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, SW7 2AZ, United Kingdom.
3
School of Health and Related Research, The University of Sheffield, 30 Regent Court, Sheffield, S10 2TA, United Kingdom.
4
Genetics and Genomic Medicine, University College London Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, United Kingdom.
5
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, OX3 7BN, United Kingdom.
6
Genomics Plc, King Charles House, Oxford, Park End Street, OX1 1JD, United Kingdom.
7
Centre for Computational Biology, Medical School, University of Birmingham, Birmingham, B15 2TT, United Kingdom.
8
The Australian National Phenome Centre, Murdoch University, Perth, WA6150, Australia.
9
Faculty of Medical Sciences, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, United Kingdom.
10
Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, 5005, Australia.
11
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 4, 08028, Barcelona, Spain.
12
McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
13
Sorbonne University, University Paris Descartes, University Paris Diderot, INSERM UMR_S 1138, Cordeliers Research Centre, 75006, Paris, France. dominique.gauguier@inserm.fr.
14
Computational and Systems Medicine, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, London, SW7 2AZ, United Kingdom. dominique.gauguier@inserm.fr.
15
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, OX3 7BN, United Kingdom. dominique.gauguier@inserm.fr.
16
McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada. dominique.gauguier@inserm.fr.

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.

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