The acyl-CoA thioesterase I is regulated by PPARα and HNF4α via a distal response element in the promoter
The acyl-CoA thioesterase I is regulated by PPARα and HNF4α via a distal response element in the promoter
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DOI：
10.1194/jlr.m700119-jlr200
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发表时间：
2007-08-01
影响因子：
6.5
通讯作者：
Hunt, Mary C.
中科院分区：
文献类型：
--
作者：
Dongol, Bikesh;Shah, Yatrik;Hunt, Mary C.
胞质酰基辅酶A硫酯酶I（Acot 1）是将链长为C-12-C-20-CoA的长链酰基CoA水解为游离脂肪酸和CoA的酶。先前已证明贝特类药物在啮齿类动物的mRNA和蛋白水平上强烈上调Acot 1。在这项研究中，我们发现，Acot 1 mRNA水平增加了90倍，在肝脏中的Wy-14，643治疗，Acot 1 mRNA也增加了15倍，在肝细胞核因子4 α（HNF 4 α）基因敲除动物的肝脏。我们的研究确定了一个直接重复序列1（DR 1）位于Acot 1基因启动子在小鼠，它结合过氧化物酶体增殖物激活受体α（PPAR α）和HNF 4a。染色质免疫沉淀（ChIP）分析显示，鉴定的DR 1结合PPARa/维甲酸X受体a（RXR α）和HNF 4a，而ChIP中的结合在PPARa和HNF 4a敲除小鼠模型中被废除。报告基因分析显示，在与PPAR α/RXR α共转染后，细胞中的Acot 1启动子被PPARa激动剂Wy-14，643激活。然而，用含有HNF 4a的质粒转染也导致启动子活性的增加。总之，这些数据表明Acot 1受到HNF 4a和PPARa之间相互作用的调节。
The cytosolic acyl-coenzyme A thioesterase I (Acot1) is an enzyme that hydrolyzes long-chain acyl-CoAs of C-12-C-20-CoA in chain length to the free fatty acid and CoA. Acot1 was shown previously to be strongly upregulated at the mRNA and protein level in rodents by fibrates. In this study, we show that Acot1 mRNA levels were increased by 90-fold in liver by treatment with Wy-14,643 and that Acot1 mRNA was also increased by 15-fold in the liver of hepatocyte nuclear factor 4 alpha (HNF4 alpha) knockout animals. Our study identified a direct repeat 1 (DR1) located in the Acot1 gene promoter in mouse, which binds the peroxisome proliferator-activated receptor a (PPAR alpha) and HNF4a. Chromatin immunoprecipitation (ChIP) assay showed that the identified DR1 bound PPAR alpha/retinoid X receptor a (RXR alpha) and HNF4a, whereas the binding in ChIP was abrogated in the PPARa and HNF4a knockout mouse models. Reporter gene assays showed activation of the Acot1 promoter in cells by the PPARa agonist Wy-14,643 after cotransfection with PPAR alpha/RXR alpha. However, transfection with a plasmid containing HNF4a also resulted in an increase in promoter activity. Together, these data show that Acot1 is under regulation by an interplay between HNF4a and PPARa.