The PERK/eIF2α/ATF4/CHOP pathway plays a role in regulating monocrotaline-induced endoplasmic reticulum stress in rat liver.

Monocrotaline (MCT) belongs to the category of Pyrrolizdine Alkaloids (PAs), which is one of important hepatotoxic alkaloid in Crotalaria Lin. Apoptosis is one mechanism of toxic responses induced by MCT. However, the underlying mechanism of liver apoptosis caused by MCT through Endoplasmic reticulum (ER) stress continues to be incompletely understood. In this study, we describe the role of ER stress in MCT induced hepatotoxicity in rats. 24 male rats were randomly divided into 3 groups: normal saline group, 45 mg/kg MCT group and 90 mg/kg MCT group. After 48 h of saline/MCT administration, the livers were collected for analysis of ER stress-related proteins by Western blotting. The expression of GRP78, p-IRE1α, ATF6 and caspase-12 showed a dose-dependent increase. PERK/eIF2α/ATF4/CHOP pathway is one of the major ER stress pathways which is required for cell survival. Therefore, through analyzing the effects of MCT on this pathway, we found the protein levels of p-PERK, p-eIF2α, ATF4 and CHOP were increase obviously. All these results indicate that MCT induces ER stress in rat liver. The PERK/eIF2α/ATF4/CHOP pathway is involved in the regulation of MCT-induced ER stress in the liver of rat.

Guo Y ，Guo R ，Su Y ，Fu J ，Wang S ，Kong Y ，Wu C ，Wang J ，Tan C ，Mo C ，Zhao B ... -  《-》

Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2α-ATF4-CHOP pathway.

Pyrazinamide (PZA)-induced serious liver injury, but the exact mechanism of PZA-induces hepatotoxicity remains controversial. Endoplasmic reticulum (ER) stress-caused cell apoptosis plays a critical role in the development of drug-induced liver injury (DILI). However, the direct connection between PZA toxicity and ER stress is unknown. In this study, we describe the role of ER stress in PZA induced hepatotoxicity in vivo and in vitro. We found that PZA induces apoptosis in HepG2 cells, and causes liver damage in rats, characterized by increased serum ALT, AST and TBA levels. PZA impairs antioxidant defenses, although this effect did not play an important role in resulting liver injury. The ER stress related proteins GRP78, p-PERK, p-eIF2α, ATF4, CHOP and caspase12 were activated after PZA exposure both in vivo and in vitro. Furthermore, as an ER stress inhibitor, sodium 4-phenylbutyrate (4-PBA) could ameliorate PZA toxicity in HepG2 cells and rat liver. These results have potential implications for the pathogenesis of PZA-induced hepatotoxicity in which ER stress especially PERK-eIF2α-ATF4-CHOP pathway participates in hepatocellular injury.

Guo HL ，Hassan HM ，Ding PP ，Wang SJ ，Chen X ，Wang T ，Sun LX ，Zhang LY ，Jiang ZZ ... -  《-》

Pollen Typhae Total Flavone Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis in Human Aortic-Vascular Smooth Muscle Cells through Down-Regulating PERK-eIF2α-ATF4-CHOP Pathway.

Chen MT ，Huang RL ，Ou LJ ，Chen YN ，Men L ，Chang X ，Wang L ，Yang YZ ，Zhang Z ... -  《-》

Psoralen induces hepatic toxicity through PERK and ATF6 related ER stress pathways in HepG2 cells.

Yu Y ，Yu R ，Men W ，Zhang P ，Zhang Y ，Song L ，Zhou K ... -  《-》

ROS-mediated PERK-eIF2α-ATF4 pathway plays an important role in arsenite-induced L-02 cells apoptosis via regulating CHOP-DR5 signaling.

Chronic exposure to arsenic remains a worldwide environmental health issue, affecting hundreds of millions of people. Although, arsenic-induced oxidative stress and apoptosis have been determined, the underlying apoptosis mechanism has not been fully elucidated yet. Oxidative stress integrated-ER stress plays an important role in Life-and-Death decision of cells. The current study was to investigate whether NaAsO2 utilizes oxidative stress integrated-ER stress signaling to exert pro-apoptotic activity in L-02 cells. Results showed that death receptor 5 (DR5) was a mediator of NaAsO2 -induced apoptosis by enhancing construction of the death-inducing signaling complex (DISC). NaAsO2 -sensitized DR5 elevation required maintainable transcription and its transcription factor C/EBP homologous protein (CHOP). Further results showed that NaAsO2 increased expression in biomarker of endoplasmic reticulum (ER) stress and activated the protein kinase R-like ER kinase (PERK)-eukaryotic translation initiation 2α (eIF2α)-activating transcription factor 4 (ATF4) pathway. PERK inhibitor and ATF4 siRNA significantly attenuated NaAsO2 -induced CHOP and DR5 expressions. In addition, the antioxidant N-acetyl-l-cysteine (NAC) treatment led to amelioration of NaAsO2 -induced production of reactive oxygen species (ROS) and some ER stress- and apoptosis- related protein levels and cell viability. Taken together, the results indicate that ROS-mediated PERK-eIF2α-ATF4 pathway activated by NaAsO2 is the critical upstream event for subsequent apoptosis induction via regulating CHOP-DR5 signaling in L-02 cells when chronic exposure to arsenic, and support that antioxidants might be potential therapeutic agents for preventing or delaying the onset and progress of arsenic-induced hepatotoxicity.

Liu C ，Zhang A 《-》