核受体,组成型雄甾烷受体(CAR),与类视黄醇X受体(RXR)形成异二聚体,最初被报道为调节参与解毒和能量代谢的肝脏基因的转录因子。不同的研究表明,CAR激活会导致代谢紊乱,包括非酒精性脂肪肝,通过激活肝脏中的脂肪生成。我们的目标是确定CAR/RXR异二聚体的协同激活是否可以如其他作者在体外描述的那样在体内发生。并评估代谢后果。为此,六种杀虫剂,CAR的配体,被选中,和三丁基锡(TBT)用作RXR激动剂。在老鼠身上,与TBT相关的狄氏剂诱导CAR的协同激活,联合作用是由丙环唑诱导的,bifenox,boscalid,和成虫。此外,脂肪变性,以甘油三酯增加为特征,当TBT与狄氏剂结合使用时观察到,丙环唑,bifenox,boscalid,和成虫。代谢破坏以胆固醇增加和游离脂肪酸血浆水平降低的形式出现。深入分析显示与脂质合成和脂质输入有关的基因表达增加。这些结果有助于人们越来越了解环境污染物如何影响核受体活性和相关的健康风险。
The nuclear receptor, constitutive androstane receptor (CAR), which forms a heterodimer with the retinoid X receptor (
RXR), was initially reported as a transcription factor that regulates hepatic genes involved in detoxication and energy metabolism. Different studies have shown that CAR activation results in metabolic disorders, including non-alcoholic fatty liver disease, by activating lipogenesis in the liver. Our objective was to determine whether synergistic activations of the CAR/
RXR heterodimer could occur in vivo as described in vitro by other authors, and to assess the metabolic consequences. For this purpose, six pesticides, ligands of CAR, were selected, and Tri-butyl-tin (TBT) was used as an
RXR agonist. In mice, CAR\'s synergic activation was induced by dieldrin associated with TBT, and combined effects were induced by propiconazole, bifenox, boscalid, and bupirimate. Moreover, a steatosis, characterized by increased triglycerides, was observed when TBT was combined with dieldrin, propiconazole, bifenox, boscalid, and bupirimate. Metabolic disruption appeared in the form of increased cholesterol and lowered free fatty acid plasma levels. An in-depth analysis revealed increased expression of genes involved in lipid synthesis and lipid import. These results contribute to the growing understanding of how environmental contaminants can influence nuclear receptor activity and associated health risks.