Inhibiting alpha subunit of eukaryotic initiation factor 2 dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation in acute liver injury

Chen, Guimei; Yang, Xuemei; He, Yi-Huai; Tang, Yong-Jing; Tian, Ren-Dong; Huang, Weicai; Chen, Huan; Yang, Feifei; Liu, Ying; Lin, Shide

doi:10.3325/cmj.2019.60.532

Cited by 4 publications

(4 citation statements)

References 33 publications

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“…ER stress is closely related to cell apoptosis, necroptosis and cell proliferation [26][27][28]. Earlier, we reported that ER stress affects hepatocyte apoptosis [24], necroptosis [22] and cell proliferation [23,29]. In this study, TG induced ER stress, triggered apoptosis and necroptosis, and inhibited cell proliferation in hepatocellular carcinoma cells.…”

Section: Discussionsupporting

confidence: 50%

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Chen

Liu

et al. 2021

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Alpha-fetoprotein (AFP) and endoplasmic reticulum (ER) stress play multiple roles in hepatocellular carcinoma. Here, we analyzed the crosstalk between AFP and ER stress in human hepatoma cells. We induced ER stress in human hepatoma cell lines (HepG2 and SK-Hep1 cells) with thapsigargin (TG, an ER stress inducer), and mitigated ER stress with 4-phenylbutyrate acid (4-PBA, an ER stress inhibitor). AFP expression was knocked down by AFP short hairpin RNA and rescued by the pCI-AFP vector. AFP expression and ER stress were examined, and their roles in apoptosis, necroptosis, and proliferation were analyzed. TG significantly induced ER stress, apoptosis, necroptosis, and intracellular AFP protein levels, and reduced proliferation and AFP mRNA expression as well as supernatant AFP protein levels in HepG2 and SK -Hep1 cells. 4-PBA pretreatment partially reversed those changes in HepG2 cells. By contrast to AFP overexpression, knockdown of AFP significantly exacerbated TG-induced ER stress, apoptosis, and necroptosis, and decreased proliferation and the expression of activating transcription factor 6 alpha. In conclusion, ER stress causes the accumulation of AFP protein, which may be related to the reduction of AFP secretion. Accumulated AFP mitigates apoptosis and necroptosis and restores the proliferation of hepatoma cells by reducing ER stress.

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Section: Discussionsupporting

confidence: 50%

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Chen

Liu

et al. 2021

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“…However, the crosstalk between ER stress and necroptosis and its significance remain unknown. The efficacy of the experimental models, for example, using CCl 4 and TM to induce acute liver injury in mice and the TG-induced ER stress in LO2 cells, was validated in previous reports, and it was previously verified that ER stress mediates necroptosis [30,[41][42][43]. CCl 4 is a well-documented hepatotoxin that induces acute liver injury by oxidative damage via its free radical metabolites [44][45][46].…”

Section: Discussionmentioning

confidence: 74%

Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model

Huang

Wan

Deng

et al. 2021

BioMed Research International

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Background. Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model. Methods. In vivo and in vitro experiments were carried out. LO2 cells were treated with thapsigargin (TG). In vivo, male BALB/c mice were treated with carbon tetrachloride (CCl4, 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER stress-related protein expression was examined. Results. TG induced ER stress and necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 significantly decreased RIP3 expression ( p < 0.05 ) and increased ER stress and necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER stress ( p < 0.05 ). Similar results were observed in CCl4 or the TM-induced mouse model. The knockdown of ATF6 significantly decreased CCl4-induced RIP3 expression and increased liver injury, necroptosis, and ER stress in mice livers ( p < 0.05 ). In contrast, the downregulation of RIP3 significantly reduced liver injury, hepatocyte necroptosis, and ER stress. Conclusions. Hepatocyte ATF6 has multiple roles in acute liver injury. It reduces hepatocyte necroptosis via negative feedback regulation of ER stress. In addition, ATF6 can upregulate the expression of RIP3, which is not helpful to the recovery process. However, downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation of ER stress. The findings suggest that RIP3 could be a plausible target for the treatment of liver injury.

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“…After reaction with horseradish peroxidase (HRP)-conjugated anti-mouse or anti-rabbit IgG, the immunocomplexes were visualized with enhanced chemiluminescent reagents. Quantity One software (Bio-Rad, Hercules, CA, United States) was used to determine the relative levels of each targeted protein to the control (standardized as 1)[ 18 ].…”

Section: Methodsmentioning

confidence: 99%

Intracellular alpha-fetoprotein mitigates hepatocyte apoptosis and necroptosis by inhibiting endoplasmic reticulum stress

Yun-fen¹,

Liu²,

Cheng³

et al. 2022

WJG

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BACKGROUND Endoplasmic reticulum (ER) stress contributes to the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified. Alpha-fetoprotein (AFP) is secreted by hepatoma cells and elevated levels of serum AFP are associated with development of liver malignancies. AIM To investigate whether and how AFP could regulate ER stress and hepatocyte injury. METHODS The distribution of AFP and the degrees of ER stress in liver tissues and liver injury were characterized by histology, immunohistochemistry, and Western blot in biopsied human liver specimens, two mouse models of liver injury and a cellular model. The levels of AFP in sera and the supernatants of cultured cells were quantified by chemiluminescence. RESULTS High levels of intracellular AFP were detected in liver tissues, particularly in the necrotic areas, from patients with chronic liver diseases and mice after carbon tetrachloride (CCl 4 ) administration or induction of ER stress, but not from the controls. The induced intracellular AFP was accompanied by elevated activating transcription factor-6 (ATF6) expression and protein kinase R-like ER kinase (PERK) phosphorylation in mouse livers. ER stress induced AFP expression in LO2 cells and decreased their viability. ATF6, but not PERK, silencing mitigated the ER-stress-induced AFP expression in LO2 cells. Conversely, AFP silencing deteriorated the ER stress-mediated LO2 cell injury and CCl 4 administration-induced liver damages by increasing levels of cleaved caspase-3, the C/enhancer binding protein homologous protein expression, mixed lineage kinase domain-like pseudokinase and PERK phosphorylation, but decreasing ATF6 expression. CONCLUSION ER stress upregulated intra-hepatocyte AFP expression by activating ATF6 during the process of liver injury and intracellular AFP attenuated hepatocyte apoptosis and necroptosis by alleviating ER stress.

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Inhibiting alpha subunit of eukaryotic initiation factor 2 dephosphorylation protects injured hepatocytes and reduces hepatocyte proliferation in acute liver injury

Cited by 4 publications

References 33 publications

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Alpha-fetoprotein/endoplasmic reticulum stress signaling mitigates injury in hepatoma cells

Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model

Intracellular alpha-fetoprotein mitigates hepatocyte apoptosis and necroptosis by inhibiting endoplasmic reticulum stress

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