PDF(Pubmed)
Abstract：
This study explores the impact of environmental pollutants on nuclear receptors (CAR, PXR, PPARα, PPARγ, FXR, and LXR) and their heterodimerization partner, the Retinoid X Receptor (RXR). Such interaction may contribute to the onset of non-alcoholic fatty liver disease (NAFLD), which is initially characterized by steatosis and potentially progresses to steatohepatitis and fibrosis. Epidemiological studies have linked NAFLD occurrence to the exposure to environmental contaminants like PFAS. This study aims to assess the simultaneous activation of nuclear receptors via perfluorooctanoic acid (PFOA) and RXR coactivation via Tributyltin (TBT), examining their combined effects on steatogenic mechanisms. Mice were exposed to PFOA (10 mg/kg/day), TBT (5 mg/kg/day) or a combination of them for three days. Mechanisms underlying hepatic steatosis were explored by measuring nuclear receptor target gene and lipid metabolism key gene expressions, by quantifying plasma lipids and hepatic damage markers. This study elucidated the involvement of the Liver X Receptor (LXR) in the combined effect on steatosis and highlighted the permissive nature of the LXR/RXR heterodimer. Antagonistic effects of TBT on the PFOA-induced activation of the Pregnane X Receptor (PXR) and Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) were also observed. Overall, this study revealed complex interactions between PFOA and TBT, shedding light on their combined impact on liver health.
摘要：
本研究探讨了环境污染物对核受体(CAR，PXR,PPARα,PPARγ,FXR,和LXR)和它们的异二聚体伴侣，视黄醇X受体(RXR)。这种相互作用可能有助于非酒精性脂肪性肝病（NAFLD）的发作，其最初的特征是脂肪变性，并可能发展为脂肪性肝炎和纤维化。流行病学研究已将NAFLD的发生与PFAS等环境污染物的暴露联系起来。这项研究旨在评估通过全氟辛酸（PFOA）和通过三丁基锡（TBT）的RXR共激活核受体的同时激活，检查它们对脂肪生成机制的综合影响。将小鼠暴露于PFOA（10mg/kg/天），TBT（5mg/kg/天）或它们的组合持续三天。通过测量核受体靶基因和脂质代谢关键基因的表达来探索肝脏脂肪变性的机制。通过定量血浆脂质和肝损伤标志物。这项研究阐明了肝脏X受体（LXR）对脂肪变性的联合作用，并强调了LXR/RXR异二聚体的允许性质。还观察到TBT对PFOA诱导的孕烷X受体（PXR）和过氧化物酶体增殖物激活受体γ（PPARγ）激活的拮抗作用。总的来说,这项研究揭示了PFOA和TBT之间的复杂相互作用，阐明它们对肝脏健康的综合影响。
