Response of rat liver to GW7647

Activation of PPARa pathways by some environmental chemicals causes hepatocyte proliferation and cancer in rodents. While these responses do not seem to occur in humans, the biological basis of these species differences remains uncertain. We systematically evaluated multiple readouts in rat and human hepatocytes and gene expression in intact rat livers using a PPARa-selective agonist, GW7467. In vitro rat hepatocytes had more genes significantly altered by GW7647 than did human (2320 versus 192). There were common pathways of fatty acid metabolism, amino acid metabolism and lipid transport, mostly represented by upregulated genes, shared between species. In rat hepatocytes, there were many downregulated genes enriched for processes including apoptosis, inflammation, response to hormones and chemical stimuli. In vivo, gene expression signatures for proliferation were present at high doses. In both species, a third of the genes with altered expression had direct binding of PPARa to a nearby peroxisome proliferator response element (PPRE). While the PPRE associated with upregulated genes in both species, was similar, the downregulated genes in the rat had altered flanking region conservation of nucleotides. Among the down regulated genes with direct PPARa binding in the rat were two key transcription factors – Hnf6 (onecut1) and Ets. Our results support a qualitative difference in biology of PPARa activation between human and rats. The secondary downregulated pathways, in the rat, appear to be reversion to an earlier lineage more responsive to proliferative signals that likely arise from interactions between the PPARa activated hepatocytes and other cell types in the intact liver.部分环境化学物激活过氧化物酶体增殖物激活受体α（PPARa）通路，可诱发啮齿类动物肝细胞增殖与癌变。尽管此类效应似乎并未在人类中出现，但造成这些物种差异的生物学基础仍未明确。本研究采用PPARa选择性激动剂GW7467，系统评估了大鼠与人类肝细胞的多种检测终点，以及完整大鼠肝脏的基因表达情况。体外实验中，经GW7647处理的大鼠肝细胞中，发生显著表达变化的基因数量多于人类肝细胞（分别为2320个与192个）。两个物种共享的通路主要包括脂肪酸代谢、氨基酸代谢与脂质转运，且这些通路的基因大多呈上调表达。在大鼠肝细胞中，大量下调基因富集于细胞凋亡、炎症反应、激素应答与化学刺激应答等生物学过程。体内实验中，高剂量给药组可检测到与细胞增殖相关的基因表达特征。在两个物种中，三分之一表达发生变化的基因，其邻近区域存在PPARa与过氧化物酶体增殖物应答元件（PPRE）的直接结合。尽管两个物种中与上调基因相关的PPRE序列相似，但大鼠体内的下调基因，其侧翼区域的核苷酸保守性发生了改变。在大鼠体内经PPARa直接结合的下调基因中，包含两个关键转录因子——Hnf6（onecut1）与Ets。本研究结果证实，人类与大鼠在PPARa激活后的生物学效应存在质性差异。大鼠体内的次级下调通路，似乎是向更早的细胞谱系逆转，这类谱系对增殖信号的敏感性更高；而此类增殖信号大概率来源于PPARa激活的肝细胞与完整肝脏内其他细胞类型之间的相互作用。