Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with metabolic disruption and nonalcoholic fatty liver disease (NAFLD). Based on their ability to activate the aryl hydrocarbon receptor (AhR), PCBs are subdivided into two classes: dioxin-like (DL) and non-dioxin-like (NDL) PCBs. Previously, we demonstrated that NDL PCBs compromised the liver to promote more severe diet-induced NAFLD. Here, the hepatic effects and potential mechanisms (by untargeted liver proteomics) of DL PCBs and NDL PCBs or co-exposure to both in diet-induced NAFLD are investigated. Male C57Bl/6 mice were fed a 42% fat diet and exposed to vehicle control; Aroclor1260 (20 mg/kg, NDL PCB mixture); PCB126 (20 μg/kg, DL PCB congener); or a mixture of Aroclor1260 (20 mg/kg) + PCB126 (20 μg/kg) for 12 weeks. Each exposure was associated with a distinct hepatic proteome. Phenotypic and proteomic analyses revealed increased hepatic inflammation and phosphoprotein signaling disruption by Aroclor1260. PCB126 decreased hepatic inflammation and fibrosis at the molecular level; while altering cytoskeletal remodeling, metal homeostasis, and intermediary/xenobiotic metabolism. PCB126 attenuated Aroclor1260-induced hepatic inflammation but increased hepatic free fatty acids in the co-exposure group. Aroclor1260 + PCB126 exposure was strongly associated with multiple epigenetic processes, and these could potentially explain the observed nonadditive effects of the exposures on the hepatic proteome. Taken together, the results demonstrated that PCB exposures differentially regulated the hepatic proteome and the histologic severity of diet-induced NAFLD. Future research is warranted to determine the AhR-dependence of the observed effects including metal homeostasis and the epigenetic regulation of gene expression.

中文翻译：

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二恶英样和非二恶英样多氯联苯对肝脏蛋白质组有不同的调节作用，并改变饮食引起的非酒精性脂肪肝疾病的严重程度。


多氯联苯 (PCB) 是一种持久性有机污染物，与代谢紊乱和非酒精性脂肪肝 (NAFLD) 相关。根据其激活芳烃受体 (AhR) 的能力，PCB 分为两类：二恶英类 (DL) 和非二恶英类 (NDL) PCB。此前，我们证明 NDL PCB 会损害肝脏，从而促进更严重的饮食诱发的 NAFLD。在此，研究了 DL PCB 和 NDL PCB 或同时暴露于两者在饮食诱导的 NAFLD 中的肝脏影响和潜在机制（通过非靶向肝脏蛋白质组学）。雄性 C57Bl/6 小鼠喂食 42% 脂肪饮食并暴露于载体对照； Aroclor1260（20 mg/kg，NDL PCB 混合物）； PCB126（20 μg/kg，DL PCB 同系物）；或 Aroclor1260 (20 mg/kg) + PCB126 (20 μg/kg) 的混合物，持续 12 周。每次暴露都与独特的肝脏蛋白质组相关。表型和蛋白质组分析显示 Aroclor1260 增加了肝脏炎症和磷蛋白信号传导破坏。 PCB126在分子水平上减少肝脏炎症和纤维化；同时改变细胞骨架重塑、金属稳态和中间/外源代谢。 PCB126 减轻了 Aroclor1260 诱导的肝脏炎症，但在共同暴露组中增加了肝脏游离脂肪酸。 Aroclor1260 + PCB126 暴露与多种表观遗传过程密切相关，这些可能可以解释观察到的暴露对肝蛋白质组的非加性效应。总而言之，结果表明 PCB 暴露对肝脏蛋白质组和饮食诱发的 NAFLD 的组织学严重程度有不同的调节作用。 未来的研究有必要确定观察到的影响的 AhR 依赖性，包括金属稳态和基因表达的表观遗传调控。