Critical role of caveolin-1 in aflatoxin B1-induced hepatotoxicity via the regulation of oxidation and autophagy

Qingqiang Xu,Xiaowen He,Hua Han,Pan Lv,Mingxue Sun,Kai Xiao,Wenqi Meng,Chuchu Gong,Wenwen Shi,Guanchao Mao,Jie Zhao,Yongchun Chen,Youheng Wei

doi:10.1038/s41419-019-2197-6

Qingqiang Xu, Xiaowen He + Show 11 more

Open Access

https://doi.org/10.1038/s41419-019-2197-6

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Abstract

Aflatoxin B1 (AFB1) is a potent hepatocarcinogen in humans and exposure to AFB1 is known to cause both acute and chronic hepatocellular injury. As the liver is known to be the main target organ of aflatoxin, it is important to identify the key molecules that participate in AFB1-induced hepatotoxicity and to investigate their underlying mechanisms. In this study, the critical role of caveolin-1 in AFB1-induced hepatic cell apoptosis was examined. We found a decrease in cell viability and an increase in oxidation and apoptosis in human hepatocyte L02 cells after AFB1 exposure. In addition, the intracellular expression of caveolin-1 was increased in response to AFB1 treatment. Downregulation of caveolin-1 significantly alleviated AFB1-induced apoptosis and decreased cell viability, whereas overexpression of caveolin-1 reversed these effects. Further functional analysis showed that caveolin-1 participates in AFB1-induced oxidative stress through its interaction with Nrf2, leading to the downregulation of cellular antioxidant enzymes and the promotion of oxidative stress-induced apoptosis. In addition, caveolin-1 was found to regulate AFB1-induced autophagy. This finding was supported by the effect that caveolin-1 deficiency promoted autophagy after AFB1 treatment, leading to the inhibition of apoptosis, whereas overexpression of caveolin-1 inhibited autophagy and accelerated apoptosis. Interestingly, further investigation showed that caveolin-1 participates in AFB1-induced autophagy by regulating the EGFR/PI3K-AKT/mTOR signaling pathway. Taken together, our data reveal that caveolin-1 plays a crucial role in AFB1-induced hepatic cell apoptosis via the regulation of oxidation and autophagy, which provides a potential target for the development of novel treatments to combat AFB1 hepatotoxicity.

Highlights

Aflatoxins are secondary metabolites with high toxicity produced by different strains of fungi, such as Aspergillus flavus and Aspergillus parasiticus, and are a common dietary contaminant all over the world, especially in tropical and subtropical regions[1]
To directly detect the cytotoxicity induced by Aflatoxin B1 (AFB1), L02 cells were treated with increasing concentrations of AFB1 or treated with AFB1 for different durations, and the cell viability was measured by Cell Counting Kit-8 (CCK-8) assay
These results indicate that AFB1 exposure induces oxidative stress and apoptosis, leading to a decrease in cell viability

Summary

Introduction

Aflatoxins are secondary metabolites with high toxicity produced by different strains of fungi, such as Aspergillus flavus and Aspergillus parasiticus, and are a common dietary contaminant all over the world, especially in tropical and subtropical regions[1]. ROS at physiological levels play an important role in normal cellular signaling to induce adaptive responses. High levels of ROS lead to cell death by inducing oxidative damage to susceptible proteins and lipids[5]. AFB1 can impair the antioxidant/prooxidant imbalance and elevate lipid peroxidation, resulting in the damage of biological molecules including lipids, proteins, and DNA in cellular systems[8]. The combination of these effects leads to the activation of a programmed cell death process or induces cells to produce potentially catastrophic genetic alterations, which depend on the dose and duration of AFB1 exposure[9,10]. The precise mechanism of AFB1-induced oxidative damage is not well understood, especially the key molecules and pathways that participate in this process in response to AFB1 stimulation

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