Gene expression profiling in livers of mice after acute inhibition of beta-oxidation.
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.
van der Leij
Feike R
FR
Center for Liver, Digestive, and Metabolic Diseases, Laboratory of Pediatrics, University Medical Center Groningen, University of Groningen, CMCV, Groningen, The Netherlands.
Bloks
Vincent W
VW
Grefhorst
Aldo
A
Hoekstra
Jildou
J
Gerding
Albert
A
Kooi
Krista
K
Gerbens
Frans
F
te Meerman
Gerard
G
Kuipers
Folkert
F
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
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