Aristolochic acid-induced dyslipidemia and hepatotoxicity: The potential role of FXR and AHR receptors

IF 6.2 2区环境科学与生态学 Q1 ENVIRONMENTAL SCIENCES

Ecotoxicology and Environmental Safety Pub Date : 2024-11-06 DOI:10.1016/j.ecoenv.2024.117266

Yumei Ma , Chenlong Du , Yuzhen Liu , Meiyao Feng , Yingqing Shou , Dianke Yu , Yuan Jin

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引用次数: 0

Abstract

Aristolochic acids (AAs) represent a class of nitrophenanthrene carboxylic acids naturally existing or accidentally mixed in herbal medicines or crops, which have long been recognized for causing nephropathy. Recently, the linkage between AAs and liver injury has become a concern; however, the current understanding of the mechanism or mode of action (MOA) is limited. In the present study, we investigated nuclear receptor-mediated MOA associated with AAs-induced liver injury including dyslipidemia and hepatotoxicity. Bioinformatic analysis of AAI-interacting genes indicated nuclear receptor-mediated metabolizing pathways; Transcriptomic profiling of AAs-exposed rats with liver injury suggested FXR-, NRF2-, and AHR- mediated pathways in the injured livers of the rats. Mechanistic investigation using HepG2 cells indicated AAI-induced hepatic lipid accumulation by elevating Triglyceride (TG) through inhibition of the FXR. In addition, AAI-induced hepatocellular damage by activating the AHR pathway, which further generated ROS and activated the NRF2 pathway. Together, these results provided new clues for researchers who are interested in chemical-induced liver injury.

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马兜铃酸诱导的血脂异常和肝毒性：FXR 和 AHR 受体的潜在作用

马兜铃酸（AAs）是一类天然存在或意外混入中药材或农作物中的硝基菲羧酸，长期以来一直被认为可导致肾病。近来，AAs 与肝损伤之间的联系引起了人们的关注；然而，目前对其作用机制或方式（MOA）的了解还很有限。在本研究中，我们调查了核受体介导的与 AAs 诱导的肝损伤（包括血脂异常和肝毒性）相关的 MOA。对 AAI 相互作用基因的生物信息学分析表明了核受体介导的代谢途径；对暴露于 AAs 的肝损伤大鼠的转录组分析表明，在损伤的大鼠肝脏中存在 FXR-、NRF2- 和 AHR-介导的途径。使用 HepG2 细胞进行的机理研究表明，AAI 通过抑制 FXR 使甘油三酯（TG）升高，从而诱导肝脏脂质积累。此外，AAI 通过激活 AHR 通路诱导肝细胞损伤，AHR 通路进一步产生 ROS 并激活 NRF2 通路。总之，这些结果为对化学物质诱导的肝损伤感兴趣的研究人员提供了新的线索。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Ecotoxicology and Environmental Safety 环境科学-毒理学

CiteScore

12.10

自引率

5.90%

发文量

1234

审稿时长

88 days

期刊介绍： Ecotoxicology and Environmental Safety is a multi-disciplinary journal that focuses on understanding the exposure and effects of environmental contamination on organisms including human health. The scope of the journal covers three main themes. The topics within these themes, indicated below, include (but are not limited to) the following: Ecotoxicology、Environmental Chemistry、Environmental Safety etc.