Background & Aims

Acetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and metabolic signals into complex cellular transcriptional programs, might act as a rheostat for APAP-toxicity.

Methods

Wildtype or conditional Ahr knockout mice lacking Ahr in hepatocytes (Alb^Δ/ΔAhr) or myeloid cells (LysM^Δ/ΔAhr) were treated with the specific Ahr ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) together with APAP.

Results

Ahr activation by ITE, which by itself was non-toxic, exacerbated APAP-induced hepatotoxicity compared to vehicle-treated controls, causing 80% vs. 0% mortality after administration of a normally sublethal APAP overdose. Of note, Ahr activation induced hepatocyte death even at APAP doses within the therapeutic range. Aggravated liver injury was associated with significant neutrophil infiltration; however, lack of Ahr in myeloid cells did not protect LysM^Δ/ΔAhr mice from exacerbated APAP hepatotoxicity. In contrast, Alb^Δ/ΔAhr mice were largely protected from ITE-induced aggravated liver damage, indicating that Ahr activation in hepatocytes, but not in myeloid cells, was instrumental for disease exacerbation. Mechanistically, Ahr activation fueled hepatic accumulation of toxic APAP metabolites by up-regulating expression of the APAP-metabolizing enzyme Cyp1a2, a direct Ahr downstream target.

Conclusions

Ahr activation in hepatocytes potentiates APAP-induced hepatotoxicity. Thus, individual exposition to environmental Ahr ligands might explain individual sensitivity to hyperacute liver failure.

中文翻译：

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肝细胞中的芳烃受体活性对小鼠超急性对乙酰氨基酚诱导的肝毒性敏感。

背景与目标

对乙酰氨基酚 (APAP) 诱导的肝损伤是急性肝功能衰竭的最常见原因之一，但缺乏对致敏危险因素的明确定义。在这里，我们研究了配体激活的转录因子芳烃受体 (Ahr) 在 APAP 诱导的肝损伤中的作用。我们假设 Ahr 将环境、饮食、微生物和代谢信号整合到复杂的细胞转录程序中，可能充当 APAP 毒性的变阻器。

方法

在肝细胞 (Alb ^{Δ/Δ Ahr} ) 或骨髓细胞 (LysM ^{Δ/Δ Ahr} ) 中缺乏 Ahr 的野生型或条件性 Ahr 敲除小鼠用特定的 Ahr 配体 2-(1'H-indole-3'-羰基)-噻唑处理-4-羧酸甲酯 (ITE) 与 APAP。

结果

ITE 的 Ahr 激活本身是无毒的，与载体处理的对照相比，它加剧了 APAP 诱导的肝毒性，在施用正常亚致死的 APAP 过量后导致 80% 和 0% 的死亡率。值得注意的是，即使在治疗范围内的 APAP 剂量下，Ahr 激活也会诱导肝细胞死亡。加重的肝损伤与显着的中性粒细胞浸润有关；然而，骨髓细胞中缺乏 Ahr 并不能保护 LysM ^{Δ/Δ Ahr}小鼠免受加剧的 APAP 肝毒性。相比之下，Alb ^{Δ/Δ Ahr}小鼠在很大程度上免受 ITE 诱导的加重肝损伤，这表明肝细胞中的 Ahr 激活，而不是骨髓细胞中的激活，有助于疾病恶化。从机制上讲，Ahr 活化通过上调 APAP 代谢酶 Cyp1a2（Ahr 的直接下游靶标）的表达来促进有毒 APAP 代谢物的肝脏积累。

结论

肝细胞中的 Ahr 激活增强了 APAP 诱导的肝毒性。因此，个体暴露于环境 Ahr 配体可能解释个体对超急性肝衰竭的敏感性。