Coactivator PGC-1α regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes
Coactivator PGC-1α regulates the fasting inducible xenobiotic-metabolizing enzyme CYP2A5 in mouse primary hepatocytes
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DOI：
10.1016/j.taap.2008.06.001
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发表时间：
2008-10-01
影响因子：
3.8
通讯作者：
Hakkola, Jukka
中科院分区：
文献类型：
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作者：
Arpiainen, Satu;Jarvenpaa, Sanna-Mari;Hakkola, Jukka
生物体的营养状态和能量平衡相关的疾病，如糖尿病，调节外源性物质，如药物，毒素和致癌物质的代谢。然而，这种调节背后的机制大多是未知的。异生物素代谢细胞色素P450（cAMP）2A 5酶已被证明是由禁食和胰高血糖素和环AMP（cAMP）诱导的，它们介导许多禁食反应。过氧化物酶体增殖物激活受体γ辅激活因子（PGC）-1 α触发许多重要的肝脏禁食效应，以响应升高的cAMP水平。在本研究中，我们能够证明cAMP通过腺病毒介导的基因转移增加CYP 2A 5转录引起PGC-1 α表达水平的协同诱导，Cyp 2a 5 '启动子构建体与PGC-1 α表达载体的共转染证明PGC-1 α能够通过肝细胞核因子（HNF）激活Cyp 2a 5转录。Cyp 2a 5基因近端启动子中的4 α应答元件。染色质免疫沉淀分析显示PGC-1 α与HNF-4 α一起结合到Cyp 2a 5近端启动子的相同区域。综上所述，PGC-1 α通过共激活转录因子HNF-4 α介导cAMP诱导的小鼠肝细胞Cyp 2A 5的表达。这强烈表明PGC-1 α是介导CYP 2A 5空腹反应的主要因素。(C)2008年爱思唯尔公司All rights reserved.
The nutritional state of organisms and energy balance related diseases such as diabetes regulate the metabolism of xenobiotics such as drugs, toxins and carcinogens. However, the mechanisms behind this regulation are mostly unknown. The xenobiotic-metabolizing cytochrome P450 (CYP) 2A5 enzyme has been shown to be induced by fasting and by glucagon and cyclic AMP (cAMP), which mediate numerous fasting responses. Peroxisome proliferator-activated receptor gamma coactivator (PGC)-1 alpha triggers many of the important hepatic fasting effects in response to elevated cAMP levels. In the present study, we were able to show that cAMP causes a coordinated induction of PGC-1 alpha expression level by adenovirus mediated gene transfer increased CYP2A5 transcription, Co-transfection of Cyp2a5' promoter constructs with PGC-1 alpha expression vector demonstrated that PGC-1 alpha is able to activate Cyp2a5 transcription through the hepatocyte nuclear factor (HNF)-4 alpha response element in the proximal promoter of the Cyp2a5 gene. Chromartin immunoprecipitation assays showed that PGC-1 alpha binds, together with HNF-4 alpha, to the same region at the Cyp2a5 proximal promoter. In conclusion, PGC-1 alpha mediates the expression of Cyp2A5 induced by cAMP in mouise hepatocytes throuch coactivation of transcription factor HNF-4 alpha. This strongly suggests that PGC-1 alpha is the major factor mediating the fasting response of CYP2A5. (C) 2008 Elsevier Inc. All rights reserved.