关键词： AHR AHR, aryl hydrocarbon receptor ALT, alanine transaminase ANOVA, analysis of variance AST, aspartate transaminase AUC, area under the curve CAR, constitutive androstane receptor CD36, cluster of differentiation 36 CYP, cytochrome P450 EPF, enrichment by protein function Endocrine disruption Environmental liver disease FDR, false discovery rate FGF21, fibroblast growth factor 21 GCR, glucocorticoid receptor GO, gene ontology H&E, hematoxylin-eosin HDL, high-density lipoprotein HFD, high fat diet IGF1, insulin-like growth factor 1 IL-6, interleukin 6 IPF, interaction by protein function LDL, low-density lipoprotein MCP-1, monocyte chemoattractant protein-1 MUP, major urinary protein NAFLD, non-alcoholic fatty liver disease NFKBIA, nuclear factor kappa-inhibitor alpha Nonalcoholic fatty liver disease PAI-1, plasminogen activator inhibitor-1 PCB, polychlorinated biphenyl PCB126 PLIN2, perilipin-2 PNPLA3, patatin-like phospholipase domain-containing protein 3 PPARα, peroxisome proliferator-activated receptor alpha PXR, pregnane-xenobiotic receptor Perilipin-2 Pheromones SGK1, serum/glucocorticoid regulated kinase TAFLD, toxicant-associated fatty liver disease TASH, toxicant-associated steatohepatitis TAT, tyrosine aminotransferase TMT, tandem mass tag VLDL, very low-density lipoprotein WT, wild type ZFP125, zinc finger protein 125 miR, microRNA nHDLc, non-HDL cholesterol

来  源：   DOI：10.1016/j.apsb.2021.10.014   PDF(Pubmed)

Abstract：
Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and Ahr -/- mice (Taconic) were fed a control diet and exposed to 3,3\',4,4\',5-pentachlorobiphenyl (PCB126) (61 nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets (Cyp1a1 and Cyp1a2) in WT but not Ahr -/-. Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in Ahr -/-. The liver proteome was impacted more so by Ahr -/- genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was Ahr-dependent. Ahr principally regulated liver metabolism (e.g., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response (e.g., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.
摘要：
二恶英样分子与内分泌干扰和肝脏疾病有关。为了更好地理解芳烃受体（AHR）生物学，在该受体的配体激活或全身遗传消融后,对小鼠进行了代谢表型分析和肝脏蛋白质组学.雄性野生型（WT）和Ahr-/-小鼠（Taconic）饲喂对照饮食并暴露于3,3'，4,4\'，5-五氯联苯（PCB126）（61nmol/kg，通过管饲法）或媒介物，持续两周。PCB126增加了WT中经典AHR靶标(Cyp1a1和Cyp1a2)的表达,但不增加Ahr-/-。敲除后肥胖增加，糖耐量降低；肝脏变小，脂肪变性和perilipin-2增加；矛盾的是血脂降低。PCB126与Ahr-/-中的肝甘油三酯增加有关。Ahr-/-基因型对肝脏蛋白质组的影响比配体激活更大，但顶级基因本体论(GO)过程相似。PCB126相关的肝脏蛋白质组是Ahr依赖性的。Ahr主要调节肝脏代谢(例如，脂质，外源性物质，有机酸)和生物能学，但它也会影响肝脏内分泌反应(例如，胰岛素受体)和功能，包括生产类固醇,肝细胞因子,和信息素结合蛋白。这些作用可能是通过相互作用转录因子或microRNA间接介导的。AHR及其配体的生物学作用需要在肝脏代谢健康和疾病方面进行更多的研究。
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