Regulation of human 3α-hydroxysteroid dehydrogenase (AKR1C4) expression by the liver x receptor α
Regulation of human 3α-hydroxysteroid dehydrogenase (AKR1C4) expression by the liver x receptor α
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DOI：
10.1124/mol.107.039099
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发表时间：
2008-02-01
影响因子：
3.6
通讯作者：
Burris, Thomas P.
中科院分区：
文献类型：
--
作者：
Stayrook, Keith R.;Rogers, Pamela M.;Burris, Thomas P.
I型人肝3 α-羟基类固醇脱氢酶（AKR 1C 4）在胆汁酸生物合成、类固醇激素代谢和异生物质代谢中起重要作用。利用隐马尔可夫模型结合染色质免疫沉淀/微阵列技术对核激素受体反应元件进行预测建模，揭示了AKR 1C 4启动子中被称为肝X受体α（LXR α [NR 1H 3]）的核激素受体的推定结合位点，该受体是氧化胆固醇代谢物的生理受体。推定的LXR α反应元件（LXRE），染色质免疫沉淀法确定，是类似于1.5的转录起始位点上游的酶对。LXR α被证明可以特异性地与该LXRE结合，并介导AKR 1C 4基因的转录激活，导致AKR 1C 4蛋白表达增加。这些数据表明，LXR α可能在CYP 7A 1下游的独特位点调节胆汁酸生物合成途径，也可能调节类固醇激素和某些外源性物质的代谢。
Type I human hepatic 3 alpha-hydroxysteroid dehydrogenase (AKR1C4) plays a significant role in bile acid biosynthesis, steroid hormone metabolism, and xenobiotic metabolism. Utilization of a hidden Markov model for predictive modeling of nuclear hormone receptor response elements coupled with chromatin immunoprecipitation/microarray technology revealed a putative binding site in the AKR1C4 promoter for the nuclear hormone receptor known as liver X receptor alpha, (LXR alpha [NR1H3]), which is the physiological receptor for oxidized cholesterol metabolites. The putative LXR alpha response element (LXRE), identified by chromatin immunoprecipitation, was similar to 1.5 kilobase pairs upstream of the transcription start site. LXR alpha was shown to bind specifically to this LXRE and mediate transcriptional activation of the AKR1C4 gene, leading to increased AKR1C4 protein expression. These data suggest that LXR alpha may modulate the bile acid biosynthetic pathway at a unique site downstream of CYP7A1 and may also modulate the metabolism of steroid hormones and certain xenobiotics.