Aryl hydrocarbon receptor attenuates cholestatic liver injury by regulating bile acid metabolism
Aryl hydrocarbon receptor attenuates cholestatic liver injury by regulating bile acid metabolism
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DOI：
10.1016/j.bbrc.2023.10.030
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发表时间：
2023-10-11
影响因子：
3.1
通讯作者：
Yang，Aiting
中科院分区：
文献类型：
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作者：
Han，Qi;Yan，Xuzhen;Yang，Aiting
胆汁淤积性肝病是指多种因素导致胆汁酸（BAs）合成、分泌受损，在肝脏内蓄积，并排泄，如不及时治疗，可导致肝纤维化、胆汁淤积性胆管炎、胆汁淤积性肝硬化，最终导致终末期肝病。目前，调节BA代谢仍然是治疗胆汁淤积性疾病的一种有前景的治疗策略。芳基碳氢化合物受体（AHR）是一种配体激活的转录因子，对慢性肝病具有深远的影响。但其在胆汁淤积性肝损伤中的作用和机制尚不清楚。因此，在这项工作中，我们利用腺相关病毒（AAV）载体介导的AHR过表达来探讨AHR对胆汁淤积性肝损伤的影响。我们发现AHR在胆汁淤积性肝病的不同阶段表达存在差异，表现出下调或保护作用的增加。在DDC饮食诱导的胆汁淤积小鼠模型中，AHR的过表达增加了体重，降低了血清总胆红素（TBil）和碱性磷酸酶（ALP），减少了肝组织中卟啉的积累，并调节了胆汁酸库。总体而言，我们的数据表明 AHR 减轻了胆汁淤积性肝损伤。 AHR 功能表明它可能在胆汁淤积的临床治疗中发挥作用。
Cholestatic liver disease is defined as the bile acids (BAs) accumulation in the liver caused by impaired synthesis, and secretion, together with excretion of BAs due to a variety of factors, which, if left untreated, can result in hepatic fibrosis, cholestatic cholangitis, cholestatic cirrhosis, eventually, end-stage liver disease. Currently, modulation of BA metabolism is still a prospective therapeutic strategy for treating the cholestatic diseases. Aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor with far-reaching effects on the chronic liver disease. However, its role and mechanism in cholestatic liver damage is still unknown. Therefore, in this work, we explored the impact of AHR on the cholestatic liver injury using AHR overexpression mediated by adeno-associated viral (AAV) vectors. We found that AHR is differentially expressed in different stages of cholestatic liver disease, showing either down-regulation or an increase in protective effects. Overexpression of AHR increased body weight, decreased serum total bilirubin (TBil) and alkaline phosphatase (ALP), reduced porphyrin accumulation in liver tissue, and regulated the bile acid pool in the cholestatic mouse model induced by DDC diet. Overall, our data indicate that AHR attenuated cholestatic liver injury. AHR function indicates that it may have an action in the clinical management of cholestasis.