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首页> 外文期刊>Genomics >Gene expression profiling in livers of mice after acute inhibition of beta-oxidation.
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Gene expression profiling in livers of mice after acute inhibition of beta-oxidation.

机译：急性抑制β-氧化后小鼠肝脏中的基因表达谱。

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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 resultsindicate 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.
机译：线粒体β-氧化的先天性错误会引起异位脂肪蓄积，特别是在肝脏中。脂肪肝与胰岛素抵抗有关，易患肝纤维化。肝脂肪蓄积的病理生理后果的因素仍不清楚。进行了通过阻断长链脂肪酸β-氧化诱导的急性脂肪肝模型的基因表达分析，以研究脂肪变性对转录组的早期影响。十四烷基缩水甘油酸（TDGA）用于不可逆地抑制肉碱棕榈酰转移酶1，这是控制线粒体β-氧化的关键酶。在雄性C57BL6 / J小鼠中，TDGA治疗在12小时内诱发了大规模的微囊性肝脂肪变性。肝长链酰基辅酶A含量的增加，特别是C16：0，C16：1和C18：1的含量增加，对转录组产生了深远的影响，这是通过无偏基因表达谱分析和定量实时PCR揭示的。结果表明编码涉及脂质，碳水化合物和氨基酸代谢的蛋白质的基因的表达发生了巨大变化。通路分析确定了转录因子和核心调节剂，例如肝细胞核因子4（HNF4），过氧化物酶体增殖物激活的受体α（PPAR-alpha）和PPARγ共激活因子1alpha（PGC-1alpha）是这些代谢适应中的关键参与者。凋亡和纤维化反应也受到影响。令人惊讶地，观察到参与肝胆盐代谢和转运的基因表达大大降低。因此，这种转录组分析为研究开辟了新途径。

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