PPARα/ACOX1 as a novel target for hepatic lipid metabolism disorders induced by per- and polyfluoroalkyl substances: An integrated approach

全氟辛酸 脂肪变性 过氧化物酶体 脂质代谢 全氟辛烷 化学 脂肪肝 生物信息学 生物化学 内科学 医学 疾病 基因 有机化学 磺酸盐
作者
Yang Wang,Ling Xi,Shijun He,Haonan Cui,Zeyu Yang,Huihui An,Lihong Wang,Peng Zou,Qing Chen,Jinyi Liu,Lin Ao,Jia Cao
出处
期刊:Environment International [Elsevier]
卷期号:178: 108138-108138 被引量:27
标识
DOI:10.1016/j.envint.2023.108138
摘要

Per- and polyfluoroalkyl substances (PFAS) are persistent and ubiquitous environmental contaminants with well-documented hepatotoxicity. However, the mechanistic linkage between PFAS exposure and non-alcoholic fatty liver disease (NAFLD) remains largely elusive.This study aimed to explore PFAS-to-NAFLD link and the relevant molecular mechanisms.The cross-sectional analyses using National Health and Nutrition Examination Survey (NHANES) data were conducted to investigate the association between PFAS exposure and NAFLD. A combination of in silico toxicological analyses, bioinformatics approaches, animal experiments, and in vitro assays was used to explore the molecular initiating events (MIEs) and key events (KEs) in PFAS-induced hepatic lipid metabolism disorders.The cross-sectional analyses with NHANES data revealed the significant association between PFAS exposure and hepatic steatosis/NAFLD. The in silico toxicological analyses showed that PPARα activation induced by perfluorooctanoic acid (PFOA) and perfluorooctane sulfonic acid (PFOS), prototypical representatives of PFAS, is the critical MIE associated with NAFLD-predominant liver diseases. Transcriptome-based bioinformatic annotation and analyses identified that transcriptional upregulation of hepatic acyl-CoA oxidase 1 (ACOX1) in PPARα-regulated peroxisomal β-oxidation pathway was the KE involved with PFOA/PFOS-perturbed hepatic lipid metabolic pathways in humans, mice and rats. The in vivo and in vitro assays further verified that ACOX1-mediated oxidative stress contributed to mitochondrial compromise and lipid accumulation in PFOA/PFOS-exposed mouse hepatocytes, which could be mitigated by co-treatment with ACOX1 inhibitor and mitochondria ROS scavenger. Additionally, we observed that besides PFOA and PFOS, hepatic ACOX1 exhibited good-fit response to short-term exposures of long-chain (C7-C10) perfluoroalkyl carboxylic acids (PFHpA, PFNA, PFDA) and perfluoroalkyl sulfonic acids (PFHpS, PFDS) in human hepatocyte spheroids through benchmark dose (BMD) modeling.Our study unveils a novel molecular target for PFAS-induced hepatic lipid metabolic disorders, shedding new light on prediction, assessment, and mitigation of PFAS hepatotoxicity.
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