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Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice
- Source :
- Diabetologia. 50(9)
- Publication Year :
- 2007
-
Abstract
- AIMS/HYPOTHESIS: 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. MATERIALS AND 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/INTERPRETATION: 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.
- Subjects :
- Male
medicine.medical_specialty
Transcription, Genetic
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
Mice, Inbred Strains
Biology
Transcriptome
Mice
Insulin resistance
Diabetes mellitus
Internal medicine
Insulin Secretion
Gene expression
Internal Medicine
medicine
Animals
Insulin
Genetic Predisposition to Disease
Pancreatic hormone
Mice, Inbred BALB C
Glucose tolerance test
medicine.diagnostic_test
Fatty liver
nutritional and metabolic diseases
Glucose Tolerance Test
medicine.disease
Animal Feed
Dietary Fats
Lipids
digestive system diseases
Diet
Fatty Liver
Kinetics
Endocrinology
Liver
lipids (amino acids, peptides, and proteins)
Insulin Resistance
Subjects
Details
- Language :
- English
- ISSN :
- 14320428 and 0012186X
- Volume :
- 50
- Issue :
- 9
- Database :
- OpenAIRE
- Journal :
- Diabetologia
- Accession number :
- edsair.doi.dedup.....35d21403c1979a56fcec7ee2a070eef7