Institut National de la Santé et de la Recherche Médicale, Unité 632, 1919 Route de Mende, F-34293 Montpellier, France.
Endocrinology. 2010 Apr;151(4):1653-61. doi: 10.1210/en.2009-1435. Epub 2010 Feb 25.
The pregnane X receptors (PXRs) and the constitutive androstane receptor (CAR) were initially isolated as nuclear receptors regulating xenobiotic metabolism and elimination, alleviating chemical insults. However, recent works suggest that these xenoreceptors play an endobiotic role in modulating hepatic lipid metabolism. In this study, we show that CAR activators]phenobarbital and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime] induce the lipogenic gene thyroid hormone-responsive spot 14 protein (THRSP) (or Spot14, S14) expression in human hepatocytes. In addition, we report that treatment of wild-type mice with mCAR activators (phenobarbital and 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene) efficiently increases thrsp expression, in contrast to CAR null mice. We demonstrate that CAR directly transactivates THRSP promoter through the direct repeat with 4-bp spacer thyroid hormone and PXR response element. Deletion or point mutations within this PXR response element led to a drastic inhibition of CAR-mediated THRSP transactivation. Gel-shift analysis revealed that the CAR/retinoid X receptor complex binds to this element. In conclusion, our results indicate that THRSP gene is a CAR and PXR target gene. Because THRSP expression correlates with lipogenesis and insulin sensitivity, our data suggest that CAR and/or PXR activating drugs and xenobiotics may promote aberrant hepatic de novo lipogenesis leading potentially to fatty liver diseases and insulin resistance.
妊娠相关 X 受体 (PXRs) 和组成型雄烷受体 (CAR) 最初被分离出来作为调节异源生物代谢和消除、减轻化学刺激的核受体。然而，最近的研究表明，这些异种受体在调节肝脏脂质代谢方面发挥着内源性作用。在这项研究中，我们表明 CAR 激动剂[苯巴比妥和 6-(4-氯苯基)咪唑[2,1-b][1,3]噻唑-5-甲酰腙 O-(3,4-二氯苄基)肟]诱导人肝细胞中脂肪生成基因甲状腺激素反应斑点 14 蛋白 (THRSP) (或 Spot14, S14) 的表达。此外，我们报告称，用 mCAR 激动剂(苯巴比妥和 1,4-双[2-(3,5-二氯吡啶氧基)]苯)治疗野生型小鼠有效地增加了 thrsp 的表达，而 CAR 缺失小鼠则没有。我们证明 CAR 通过直接重复 4 个碱基对间隔的甲状腺激素和 PXR 反应元件直接反式激活 THRSP 启动子。该 PXR 反应元件内的缺失或点突变导致 CAR 介导的 THRSP 反式激活受到严重抑制。凝胶迁移分析显示，CAR/视黄酸 X 受体复合物结合到该元件上。总之，我们的结果表明 THRSP 基因是 CAR 和 PXR 的靶基因。因为 THRSP 的表达与脂肪生成和胰岛素敏感性相关，我们的数据表明 CAR 和/或 PXR 激活药物和异源生物可能促进异常的肝脏从头脂肪生成，从而潜在地导致脂肪肝疾病和胰岛素抵抗。
