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E4bp4 regulates carboxylesterase 2 enzymes through repression of the nuclear receptor Rev-erb alpha in mice

机译：E4BP4通过抑制小鼠的核受体Rev-Erbα来调节羧基酯酶2酶

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摘要

Carboxylesterases (CES) are a family of phase I enzymes that play an important role in xenobiotic clearance and lipid metabolism. Here, we investigate a potential role of E4 promoter-binding protein 4 (E4bp4) in regulation of Ces and CPT-11 (irinotecan, a first-line drug for treating colorectal cancer) pharmacokinetics in mice. Mouse hepatoma Hepa-1c1c7 cells were transfected with Rev-erba expression plasmid or siRNA targeting E4bp4. The relative mRNA and protein levels of Ces enzymes in the cells or the livers of wild-type and E4bp4-deficient (E4bp4(-/-)) mice were determined by qPCR and Western blotting, respectively. Transcriptional regulation of Ces by E4bp4/Rev-erba were investigated using luciferase reporter, mobility shift, and co-immunoprecipitation (Co-IP) assays. Pharmacokinetic studies were performed with wild-type and E4bp4(-/-) mice after intraperitoneal injection of CPT-11. E4bp4 ablation down-regulated an array of hepatic Ces genes in mice. E4bp4 mice also showed reduced Ces-mediated metabolism and elevated systemic exposure of CPT-11, a well-known Ces substrate. Consistently, E4bp4 knockdown reduced the expression of Ces genes (Ces2b, Ces2e and Ces2f) in Hepa-1c1c7 cells. Furthermore, Rev-erba repressed the transcription of Ces2b, whereas E4bp4 antagonized this repressive action. Co-IP experiment confirmed a direct interaction between E4bp4 and Rev-erba. Through a combination of promoter analysis and mobility shift assays, we demonstrated that Rev-erba trans repressed Ces (Ces2b) through its specific binding to the -767 to -754 bp promoter region. In conclusion, E4bp4 regulates Ces enzymes through inhibition of the transrepression activity of Rev-erb alpha, thereby impacting the metabolism and pharmacokinetics of Ces substrates.
机译：羧基酯酶（CES）是一系列I酶的酶，在癫痫症清除和脂质代谢中起重要作用。在这里，我们研究E4启动子结合蛋白4（E4BP4）在CES和CPT-11调节中的潜在作用（E4BP4）（Irinotecan，用于治疗结肠直肠癌）药代动力学的药代动力学。将小鼠肝癌HEPA-1C1C7细胞用Rev-ErBA表达质粒或靶向E4BP4转染。细胞中CES酶的相对mRNA和蛋白质水平分别通过QPCR和Western印迹测定野生型和E4BP4（ - / - ）小鼠的细胞中的肝脏酶。使用荧光素酶报告，迁移率偏移和共免疫沉淀（CO-IP）测定来研究CES通过E4BP4 / Rev-ERBA对CE的转录调节。在腹腔注射CPT-11后，用野生型和E4BP4（ - / - ）小鼠进行药代动力学研究。 E4BP4消融小鼠中调节了一系列肝CES基因。 E4BP4小鼠还显示出CES介导的代谢和CPT-11的全身暴露，众所周知的CES衬底。始终如一地，E4BP4敲低降低了HEPA-1C1C7细胞中CES基因（CES2B，CES2E和CES2F）的表达。此外，Rev-erba抑制了CES2B的转录，而E4BP4拮抗这种抑制作用。 CO-IP实验证实了E4BP4和Rev-Erba之间的直接相互作用。通过启动子分析和迁移率移位测定的组合，我们证明了Rev-Erba反式压抑CES（CES2B）通过其与-767至-754bp启动子区域的特异性结合。总之，E4BP4通过抑制Rev-ERBα的抑制来调节CES酶，从而影响CES基材的代谢和药代动力学。

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  • 来源
    《Biochemical Pharmacology》 |2018年第2018期|共9页
  • 作者

    Zhao Mengjing; Zhang Tianpeng; Yu Fangjun; Guo Lianxia; Wu Baojian;

  • 作者单位

    Jinan Univ Coll Pharm Res Ctr Biopharmaceut &

    Pharmacokinet Guangzhou Guangdong Peoples R China;

    Jinan Univ Coll Pharm Res Ctr Biopharmaceut &

    Pharmacokinet Guangzhou Guangdong Peoples R China;

    Jinan Univ Coll Pharm Res Ctr Biopharmaceut &

    Pharmacokinet Guangzhou Guangdong Peoples R China;

    Jinan Univ Coll Pharm Res Ctr Biopharmaceut &

    Pharmacokinet Guangzhou Guangdong Peoples R China;

    Jinan Univ Coll Pharm Res Ctr Biopharmaceut &

    Pharmacokinet Guangzhou Guangdong Peoples R China;

  • 收录信息
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;
  • 关键词

    E4bp4; Rev-erb alpha; CES; CPT-11; Irinotecan; Pharmacokinetics;

    机译：E4bp4;rev-erb alpha;ces;cpt-11;irinotecan;药代动力学;

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