Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor α synthetic ligands in mouse liver
Induction of nuclear translocation of constitutive androstane receptor by peroxisome proliferator-activated receptor α synthetic ligands in mouse liver
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DOI：
10.1074/jbc.m707183200
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发表时间：
2007-12-14
影响因子：
4.8
通讯作者：
Reddy, Janardan K.
中科院分区：
文献类型：
--
作者：
Guo, Dongsheng;Sarkar, Joy;Reddy, Janardan K.
过氧化物酶体增殖物激活核受体过氧化物酶体增殖物激活受体α（PPARα）并增强肝脏中多个基因的转录。我们在这里报告，合成的 PPAR α 配体 Wy-14,643、环丙贝特、氯贝特等在体内诱导小鼠肝细胞中组成型雄甾烷受体 (CAR) 的核转位。腺病毒增强的绿色荧光蛋白-CAR 表达表明，PPAR α 合成配体以不依赖于 PPAR α 和 PPAR β 的方式驱动 CAR 进入肝细胞核。这种易位依赖于转录共激活因子 PPAR 结合蛋白，但不依赖于共激活因子 PRIP 和 SRC-1。 PPAR α 配体诱导的 CAR 核转位与小鼠肝脏中 Cyp2b10 mRNA 的诱导无关。 PPAR α 配体干扰 CAR 配体结合域的共激活剂募集，并减少 CAR 的组成型反式激活。 Wy-14,643和环丙贝特都占据了CAR的配体结合口袋，并采用了与CAR反向激动剂雄烯醇类似的结合模式。因此，这些观察结果首次提供信息表明 PPAR α 配体不仅充当 PPAR α 激动剂，而且可能充当 CAR 拮抗剂。
Peroxisome proliferators activate nuclear receptor peroxisome proliferator-activated receptor alpha ( PPAR alpha) and enhance the transcription of several genes in liver. We report here that synthetic PPAR alpha ligands Wy-14,643, ciprofibrate, clofibrate, and others induce the nuclear translocation of constitutive androstane receptor (CAR) in mouse liver cells in vivo. Adeno-viral-enhanced green fluorescent protein-CAR expression demonstrated that PPAR alpha synthetic ligands drive CAR into the hepatocyte nucleus in a PPAR alpha- and PPAR beta-independent manner. This translocation is dependent on the transcription coactivator PPAR-binding protein but independent of coactivators PRIP and SRC-1. PPAR alpha ligand-induced nuclear translocation of CAR is not associated with induction of Cyp2b10 mRNA in mouse liver. PPAR alpha ligands interfered with coactivator recruitment to the CAR ligand binding domain and reduced the constitutive transactivation of CAR. Both Wy-14,643 and ciprofibrate occupied the ligand binding pocket of CAR and adapted a binding mode similar to that of the CAR inverse agonist androstenol. These observations, therefore, provide information for the first time to indicate that PPAR alpha ligands not only serve as PPAR alpha agonists but possibly act as CAR antagonists.