Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts 02215, USA.
Toxicol Sci. 2024 Aug 1;200(2):324-345. doi: 10.1093/toxsci/kfae057.
Constitutive androstane receptor (CAR, Nr1i3), a liver nuclear receptor and xenobiotic sensor, induces drug, steroid, and lipid metabolizing enzymes, stimulates liver hypertrophy and hyperplasia, and ultimately, hepatocellular carcinogenesis. The mechanisms linking early CAR responses to later disease development are poorly understood. Here we show that exposure of CD-1 mice to TCPOBOP (1,4-bis[2-(3,5-dichloropyridyloxy)]benzene), a halogenated xenochemical and selective CAR agonist ligand, induces pericentral steatosis marked by hepatic accumulation of cholesterol and neutral lipid, and elevated circulating alanine aminotransferase, indicating hepatocyte damage. TCPOBOP-induced steatosis was weaker in the pericentral region but stronger in the periportal region in females compared with males. Early (1 day) TCPOBOP transcriptional responses were enriched for CAR-bound primary response genes, and for lipogenesis and xenobiotic metabolism and oxidative stress protection pathways; late (2 weeks) TCPOBOP responses included many CAR binding-independent secondary response genes, with enrichment for macrophage activation, immune response, and cytokine and reactive oxygen species production. Late upstream regulators specific to TCPOBOP-exposed male liver were linked to proinflammatory responses and hepatocellular carcinoma progression. TCPOBOP administered weekly to male mice using a high corn oil vehicle induced carbohydrate-responsive transcription factor (MLXIPL)-regulated target genes, dysregulated mitochondrial respiratory and translation regulatory pathways, and induced more advanced liver pathology. Overall, TCPOBOP exposure recapitulates histological and gene expression changes characteristic of emerging steatotic liver disease, including secondary gene responses in liver nonparenchymal cells indicative of transition to a more advanced disease state. Upstream regulators of both the early and late TCPOBOP response genes include novel biomarkers for foreign chemical-induced metabolic dysfunction-associated steatotic liver disease.
组成型雄烷受体（CAR，Nr1i3）是一种肝脏核受体和异生物质传感器，可诱导药物、类固醇和脂质代谢酶，刺激肝脏肥大和增生，最终导致肝细胞癌发生。将 CAR 早期反应与后期疾病发展联系起来的机制尚不清楚。在这里，我们表明，用 TCPOBOP（1,4-双[2-（3,5-二氯吡啶氧基）]苯），一种卤代异生物质和选择性 CAR 激动剂配体，暴露于 CD-1 小鼠中，会诱导中央区脂肪变性，其特征是肝脏中胆固醇和中性脂质的积累，以及循环丙氨酸氨基转移酶的升高，表明肝细胞损伤。与雄性相比，雌性中 TCPOBOP 诱导的中央区脂肪变性较弱，但门周区较强。早期（1 天）TCPOBOP 转录反应富含 CAR 结合的初级反应基因，以及脂生成和异生物质代谢以及氧化应激保护途径；晚期（2 周）TCPOBOP 反应包括许多 CAR 结合非依赖性二级反应基因，富含巨噬细胞激活、免疫反应以及细胞因子和活性氧的产生。晚期仅在暴露于 TCPOBOP 的雄性肝脏中特异性的上游调节剂与促炎反应和肝细胞癌进展有关。每周用高玉米油载体向雄性小鼠施用 TCPOBOP 诱导碳水化合物反应转录因子（MLXIPL）调节的靶基因、失调的线粒体呼吸和翻译调节途径，并诱导更先进的肝病理。总体而言，TCPOBOP 暴露重现了特征性的新生脂肪性肝病的组织学和基因表达变化，包括肝非实质细胞中二级基因反应，表明向更严重的疾病状态转变。早期和晚期 TCPOBOP 反应基因的上游调节剂均包括用于外来化学物质诱导的代谢功能障碍相关脂肪性肝病的新型生物标志物。
