title: Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice.
abstract: OBJECTIVE
  Complex changes in gene expression are associated with insulin resistance and non-alcoholic fatty liver disease (NAFLD) promoted by feeding a high-fat diet (HFD). We used functional genomic technologies to document molecular mechanisms associated with diet-induced NAFLD.
  
  
  METHODS
  Male 129S6 mice were fed a diet containing 40% fat (high-fat diet, HFD) for 15 weeks. Glucose tolerance, in vivo insulin secretion, plasma lipid profile and adiposity were determined. Plasma metabonomics and liver transcriptomics were used to identify changes in gene expression associated with HFD-induced NAFLD.
  
  
  RESULTS
  In HFD-fed mice, NAFLD and impaired glucose and lipid homeostasis were associated with increased hepatic transcription of genes involved in fatty acid uptake, intracellular transport, modification and elongation, whilst genes involved in beta-oxidation and lipoprotein secretion were, paradoxically, also upregulated. NAFLD developed despite strong and sustained downregulation of transcription of the gene encoding stearoyl-coenzyme A desaturase 1 (Scd1) and uncoordinated regulation of transcription of Scd1 and the gene encoding sterol regulatory element binding factor 1c (Srebf1c) transcription. Inflammatory mechanisms appeared to be stimulated by HFD.
  
  
  CONCLUSIONS
  Our results provide an accurate representation of subtle changes in metabolic and gene expression regulation underlying disease-promoting and compensatory mechanisms, collectively contributing to diet-induced insulin resistance and NAFLD. They suggest that proposed models of NAFLD pathogenesis can be enriched with novel diet-reactive genes and disease mechanisms.
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Toye
authors.affiliation: Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: M E
authors.initials: ME
authors.lastname: Dumas
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: C
authors.initials: C
authors.lastname: Blancher
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: A R
authors.initials: AR
authors.lastname: Rothwell
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: J F
authors.initials: JF
authors.lastname: Fearnside
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: S P
authors.initials: SP
authors.lastname: Wilder
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: M T
authors.initials: MT
authors.lastname: Bihoreau
authors.affiliation: Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: O
authors.initials: O
authors.lastname: Cloarec
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: I
authors.initials: I
authors.lastname: Azzouzi
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: S
authors.initials: S
authors.lastname: Young
authors.affiliation: Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: R H
authors.initials: RH
authors.lastname: Barton
authors.affiliation: Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: E
authors.initials: E
authors.lastname: Holmes
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK.
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
authors.affiliation: Faculty of Medicine, Imperial College London, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Tatoud
authors.affiliation: Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, London, UK.
authors.forename: J K
authors.initials: JK
authors.lastname: Nicholson
authors.affiliation: Faculty of Medicine, Imperial College London, London, UK.
authors.forename: J
authors.initials: J
authors.lastname: Scott
authors.affiliation: The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK. gdomi@well.ox.ac.uk.
authors.forename: D
authors.initials: D
authors.lastname: Gauguier
mesh_terms: D000821:Animal Feed; D000818:Animals; D004032:Diet; D004041:Dietary Fats; D005234:Fatty Liver / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D000078790:Insulin Secretion; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008099:Liver / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D014158:Transcription, Genetic
chemical_list: D004041:Dietary Fats; D007328:Insulin; D008055:Lipids