CHOP Regulates Endoplasmic Reticulum Stress-Mediated Hepatoxicity Induced by Monocrotaline

Abstract

Monocrotaline (MCT), a pyrrolizidine alkaloid, is the major toxin in Crotalaria, which causes cell apoptosis in humans and animals. It has been reported that the liver is a vulnerable target of MCT. However, the exact molecular mechanism of the interaction between endoplasmic reticulum (ER) stress and liver injury induced by MCT is still unclear. In this study, the cytotoxicity of MCT on primary rat hepatocytes was analyzed by a CCK-8 assay and Annexin V-FITC/PI assay. Protein expression was detected by western blotting and immunofluorescence staining. As a result, MCT significantly decreased the cell viability and mediated the apoptosis of primary rat hepatocytes. Meanwhile, MCT could also induce ER stress in hepatocytes, indicated by the expression of ER stress-related proteins, including GRP78, p-IRE1α, ATF6, p-eIF2α, ATF4, and CHOP. Pretreatment with 4-PBA, an inhibitor of ER stress, or knockdown of CHOP by siRNA could partly enhance cell viability and relieve the apoptosis. Our findings indicate that ER stress is involved in the hepatotoxicity induced by MCT, and CHOP plays an important role in this process.

Combined Hepatotoxicity and Toxicity Mechanism of Intermedine and Lycopsamine

“…In summary, we confirmed the toxicity of the Im and La mixture on HepD cells, and the hepatotoxicity was directly related to the intracellular ROS burst and the Bax/caspase-3/caspase-9/cl-PARP mitochondrial apoptosis pathway. Additionally, the previous study found monocrotaline induced hepatotoxicity with ER stress [48]. Compared to this, we observed that the Im and La mixture caused Ca 2+ overload in the cytoplasm and induced the ER-mediated PERK/eIF2α/ATF4/CHOP apoptosis pathway, which had not been reported in previous PA toxicity studies.…”

Investigation of Gynura segetum root extract (GSrE) induced hepatotoxicity based on metabolomic signatures and microbial community profiling in rats

“…Most of the PA-induced cytotoxicity occurs in the liver, and an experiment based on human hepatic sinusoidal endothelial cells confirmed that PA-induced liver injury occurs mainly in hepatic sinusoidal endothelial cells (Yang et al, 2016 ). In addition, another study by Guo et al ( 2021 ) on primary hepatocytes of rats found that PA-induced endoplasmic reticulum stress in hepatocytes may also be associated with its hepatotoxicity.…”

Endoplasmic reticulum stress-mediated cell death in cardiovascular disease

“… 62 Pretreatment with the ERS inhibitor or knockdown of CHOP partially enhances cell viability and attenuates apoptosis. 63 PERK promotes the p-eIF2α, subsequently inducing ATF4 translocation. Once ATF4 enters the nucleus, it upregulates CHOP and GADD34 levels, alters the expression of apoptotic proteins such as Bax and Bcl-2, and participates in proapoptotic processes.…”