Abstract
Objectives Protein kinase R-like ER kinase (PERK)/eukaryotic initiation factor 2 alpha (eIF2α) is an important factor along the main pathways for endoplasmic reticulum (ER) stress-mediated apoptosis. In this study, we investigated the effects of eIF2α phosphorylation on hepatocyte apoptosis and the ER stress mechanisms in acute liver injury. Methods eIF2α 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 (CCl4) administration triggered ER stress and hepatocyte apoptosis, as well as eIF2α phosphorylation in mice. Inhibition of eIF2α dephosphorylation, as the pretreatment with 4-phenylbutyric acid (chemical chaperone, ER stress inhibitor), mitigated CCl4-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 eIF2α dephosphorylation reduced ER stress and apoptosis, while PERK knockdown reduced eIF2α phosphorylation and exacerbated ER stress and apoptosis. Conclusions eIF2α phosphorylation is one of the mechanisms employed by ER stress for restoring cellular homeostasis. Inhibition of eIF2α dephosphorylation mitigates hepatocyte apoptosis by alleviating ER stress in acute liver injuries.
Highlights
Liver injury can be initiated by a variety of causes, including infection with hepatitis viruses, alcohol, drugs, metabolic abnormalities, autoimmunity, ischemia, and hypoxia [1]
The phosphorylated eIF2α selectively induces the response of activating transcription factor 4 (ATF4) [7, 8], which regulates the expression of glucoseregulated protein 78 (GRP78), growth arrest and DNA damage 34 (GADD34), and C/EBP homologous protein (CHOP)
Serum ALT levels were elevated (P < 0:01; Figure 2(a)), hepatocyte necrosis occurred (P < 0:01; Figure 2(b)), and upregulated intrahepatic p-protein kinase R-like Endoplasmic reticulum (ER) kinase (PERK), p-eIF2α, ATF4, activating transcription factor 6 (ATF6) (a 36 kD band corresponding to the cleaved form of ATF6), X-box binding protein 1 (XBP1), CHOP, and cleaved caspase-3 protein expression peaked at 24 h post-CCl4 injection (P < 0:05; Figure 2(c))
Summary
Liver injury can be initiated by a variety of causes, including infection with hepatitis viruses, alcohol, drugs, metabolic abnormalities, autoimmunity, ischemia, and hypoxia [1]. Hepatocyte injury remains the most common pathophysiological basis of various liver diseases and the main cause of liver dysfunction [2] Apoptosis, as it relates to a form of hepatocyte injury, can be triggered by intra- or extracellular signaling. ER stress is initiated when unfolded/misfolded proteins accumulate in the ER and bind to glucoseregulated protein 78 (GRP78) [3]. This particular binding event leads to phosphorylation of protein kinase R-like ER kinase (PERK) and inositol-requiring enzyme 1 alpha (IRE1α) and cleavage of the activating transcription factor 6 (ATF6) [4, 5]. Koh et al discovered that spliced XBP1 (XBP1s) is converted from a nonspliced isoform by IRE1α endonuclease, facilitating the expression of a number of unfolded protein response
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