首页> 外文期刊>Journal of receptor and signal transduction research >Adaptive gene regulation of pyruvate dehydrogenase kinase isoenzyme 4 in hepatotoxic chemical-induced liver injury and its stimulatory potential for DNA repair and cell proliferation
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Adaptive gene regulation of pyruvate dehydrogenase kinase isoenzyme 4 in hepatotoxic chemical-induced liver injury and its stimulatory potential for DNA repair and cell proliferation

机译:丙酮酸脱氢酶激酶同工酶4在肝毒性化学性肝损伤中的自适应基因调控及其对DNA修复和细胞增殖的刺激潜力

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摘要

The processes involved in the adaptation of animals to environmental factors remain unclear. We examined the mechanisms underlying the adaptive potential of the mouse against hepatotoxic chemical-induced injury. Microarray analysis revealed that ethylbenzene, a hepatotoxic chemical, upregulated PDK4 (encoding pyruvate dehydrogenase kinase isoenzyme 4) in mouse livers and that the upregulation was enhanced by previous exposure to the chemical. Although PDK4 is an energy resource regulator induced by starvation, expression of other fasting-inducible genes was unaffected. PDK4 induced by chemical stress developed hepatic accumulation of sirtuin 1 by regulating pyruvate concentration and activated the Nbn and ATM, which are critical for DNA repair and checkpoint activation. PDK4 overexpression on carbon tetrachloride (CCl _4)-induced liver injury resulted in delayed necrotic tissue recovery with cell cycle arrest and decreased γH2AX foci and micronucleus formation. PDK4 silencing on CCl_4-induced liver injury accelerated necrotic tissue recovery and increased γH2AX foci and micronucleus formation, indicating the essential role of PDK4 in DNA repair and checkpoint activation. PDK4 overexpression induced pancreas-specific transcription factor 1a (Ptf1a) upregulation and transcriptional activation of several pancreatic genes in the liver. Ptf1a overexpression by adenoviral gene delivery resulted in accelerated tissue recovery on CCl_4-induced liver injury. Our data identified PDK4 as a novel pivotal factor in adaptation to chemical stress.
机译:使动物适应环境因素的过程仍不清楚。我们检查了小鼠对肝毒性化学诱导的损伤的适应潜力的潜在机制。基因芯片分析显示,乙肝是一种具有肝毒性的化学物质,会在小鼠肝脏中上调PDK4(编码丙酮酸脱氢酶激酶同工酶4),而上次接触该化学物质会增强这种上调。尽管PDK4是饥饿引起的能量调节因子,但其他禁食诱导基因的表达不受影响。化学应激诱导的PDK4通过调节丙酮酸的浓度发展了Sirtuin 1的肝积累,并激活了Nbn和ATM,这对于DNA修复和检查点激活至关重要。 PDK4在四氯化碳(CCl _4)诱导的肝损伤上的过表达导致坏死组织恢复延迟,细胞周期停滞,γH2AX灶和微核形成减少。 PDK4对CCl_4诱导的肝损伤的沉默加速了坏死组织的恢复,并增加了γH2AX灶和微核的形成,表明PDK4在DNA修复和检查点激活中起着至关重要的作用。 PDK4过表达诱导肝脏中胰腺特异性转录因子1a(Ptf1a)的上调和转录激活。 Ptf1a腺病毒基因传递的过表达导致CCl_4诱导的肝损伤加速组织恢复。我们的数据将PDK4识别为适应化学应激的新关键因素。

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