Activation of the IRE1α Arm, but not the PERK Arm, of the Unfolded Protein Response Contributes to Fumonisin B1-Induced Hepatotoxicity

Abstract

Previous studies by us or others have shown that endoplasmic reticulum (ER) stress was activated by fumonisin 1 (FB1) exposure, which is considered to be a critical event in the FB1-induced toxic effect. However, the detailed mechanisms underlying FB1-induced ER stress-mediated liver toxicity remain elusive. The objectives of the present study were designed to address the following issues: (1) the contribution of each arm of the unfolded protein response (UPR); (2) the downstream targets of ER stress that mediated FB1-induced liver toxicity; and (3) the relationship between ER stress and oxidative stress triggered by FB1. We also investigated whether the inhibition of ER stress by its inhibitor could offer protection against FB1-induced hepatotoxicity in vivo, which has not been critically addressed previously. The results showed that the activation of the IRE1α axis, but not of the PERK axis, of UPR contributed to FB1-induced ER stress-mediated hepatocyte toxicity; the activation of the Bax/Bak-mediated mitochondrial pathway lay downstream of IRE1α to trigger mitochondrial-dependent apoptosis in response to FB1; FB1-induced oxidative stress and ER stress augmented each other through a positive feedback mechanism; tauroursodeoxycholic acid (TUDCA)-mediated ER stress inactivation is an effective approach to counteract FB1-induced hepatotoxicity in vivo. The data of the present study allow us to better understand the mechanisms of FB1-induced hepatotoxicity.

Fumonisin B1 induces chicken heterophil extracellular traps mediated by PAD4 enzyme and P2 × 1 receptor

“…Until now, more than 15 fumonisin homologues has been characterized ( Braun and Wink, 2018 ), among which fumonisin B 1 ( FB 1 ) is the most widely distributed, and the most abundant one, and has great potential health hazards to humans and animals ( Schelstraete et al, 2020 ). FB 1 exhibits hepatotoxicity, nephrotoxicity and intestinal damage ( Müller et al, 2012 ; Poersch et al, 2014 ; Gu et al, 2019 ; Chen, et al, 2020 ; Liu, et al, 2020 ). It has been reported that dietary FB 1 resulted in depressed weight gains, increased organ weights, diarrhea, thymic cortical atrophy, multifocal hepatic necrosis, biliary hyperplasia, and rickets in broiler chicks ( Ledoux et al, 1992 ; Henry et al, 2000 ; Sousa et al, 2020 ).…”

Research Progress on Fumonisin B1 Contamination and Toxicity: A Review

“…It has been suggested that this is due to the activation of the PERK-CHOP signaling pathway by FB1, which induces apoptosis [ 76 ]. The toxic effect of endoplasmic reticulum on AML12 mouse liver cells was reported to be through the IRE1α pathway, but not the PERK pathway, but the mechanism of the IRE1α signaling pathway was not described and may require further study [ 77 ]. Meanwhile, two experiments in GES-1 and AML12 mouse liver cells suggest that the endoplasmic reticulum stress pathways caused by different organs may be different, and the specificity to organs needs to be further investigated.…”

“…Meanwhile, two experiments in GES-1 and AML12 mouse liver cells suggest that the endoplasmic reticulum stress pathways caused by different organs may be different, and the specificity to organs needs to be further investigated. This report also showed that inhibition of endoplasmic reticulum stress significantly reduced the hepatotoxicity of FB1, which may be a good way to reduce the toxicity of FB1 to the liver [ 77 ].…”

Physiological and Molecular Responses in the Gill of the Swimming Crab Portunus trituberculatus During Long-Term Ammonia Stress

“…It is well-documented that both oxidative stress and ER stress can interfere with cell function and activate pro-apoptotic signaling (Chandra et al, 2000;Tabas and Ron, 2011). Moreover, oxidative stress and ER stress could accentuate each other in a positive feedback loop, which further perturbs cellular homeostasis and elicit apoptotic cell death (Liu X. et al, 2020). Expression analysis revealed that caspase-3, the executioner of apoptosis, was significantly up-regulated in all the treatment groups, indicating that long-term ammonia stress, even at the concentration as low as 2 mg l −1 (LA group), can induce apoptosis in gills of the swimming crab.…”