title: Gene expression profiling in livers of mice after acute inhibition of beta-oxidation.
abstract: Inborn errors of mitochondrial beta-oxidation cause ectopic fat accumulation, particularly in the liver. Fatty liver is associated with insulin resistance and predisposes to hepatic fibrosis. The factors underlying the pathophysiological consequences of hepatic fat accumulation have remained poorly defined. Gene expression profiling in a model of acute fatty liver disease induced by blocking long-chain fatty acid beta-oxidation was performed to study the early effects of steatosis on the transcriptome. Tetradecylglycidic acid (TDGA) was used to irreversibly inhibit carnitine palmitoyltransferase 1, a key enzyme in the control of mitochondrial beta-oxidation. TDGA treatment induced massive microvesicular hepatic steatosis within a 12-h time frame in male C57BL6/J mice. Increased hepatic long-chain acyl-CoA content, particularly of C16:0, C16:1 and C18:1, was associated with profound effects on the transcriptome as revealed by unbiased gene expression profiling and quantitative real-time PCR. The results indicate drastic changes in the expression of genes encoding proteins involved in lipid, carbohydrate, and amino acid metabolism. Pathway analysis identified transcription factors and coregulators such as hepatocyte nuclear factor 4 (HNF4), peroxisome proliferator-activated receptor-alpha (PPAR-alpha), and PPAR gamma coactivator 1alpha (PGC-1alpha ) as key players in these metabolic adaptations. Apoptotic and profibrotic responses were also affected. Surprisingly, a strong reduction in the expression of genes involved in hepatic bile salt metabolism and transport was observed. Therefore, this transcriptome analysis opens new avenues for research.
authors.affiliation: Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, University of Groningen, CMCV, Groningen, The Netherlands.
authors.forename: Feike R
authors.initials: FR
authors.lastname: van der Leij
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Aldo
authors.initials: A
authors.lastname: Grefhorst
authors.forename: Jildou
authors.initials: J
authors.lastname: Hoekstra
authors.forename: Albert
authors.initials: A
authors.lastname: Gerding
authors.forename: Krista
authors.initials: K
authors.lastname: Kooi
authors.forename: Frans
authors.initials: F
authors.lastname: Gerbens
authors.forename: Gerard
authors.initials: G
authors.lastname: te Meerman
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001647:Bile Acids and Salts / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000235:genetics; D004852:Epoxy Compounds / Q000633:toxicity; D005227:Fatty Acids / Q000633:toxicity; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D020869:Gene Expression Profiling; D007334:Insulin-Like Growth Factor I / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000235:genetics; D010084:Oxidation-Reduction; D016133:Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics
chemical_list: D000214:Acyl Coenzyme A; D000596:Amino Acids; D001647:Bile Acids and Salts; D004852:Epoxy Compounds; D005227:Fatty Acids; D024101:Mitochondrial Proteins; D014157:Transcription Factors; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C021756:2-tetradecylglycidic acid