Objectives: Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2 phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury.

Methods: eIF2 phosphorylation and apoptosis under ER stress were monitored and measured in male BALB/c mice with acute liver injury and human hepatocyte line LO2 cells.

Results: Carbon tetrachloride (CCl) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2 phosphorylation in mice. Inhibition of eIF2 dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl-induced intrahepatic ER stress, apoptosis, and liver injury. In an ER stress model of LO2 cells induced by thapsigargin (disrupting ER calcium balance), inhibition of eIF2 dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2 phosphorylation and exacerbated ER stress and apoptosis.

Conclusions: eIF2 phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2 dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293739PMC
http://dx.doi.org/10.1155/2020/2626090DOI Listing

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