Effect of the protein kinase RNA-like endoplasmic reticulum kinase pathway in endoplasmic reticulum stress on hepatic stellate cell activation and collagen type I expression

Fengyan LI; Zefeng LIU; Yuyan XIA; Wenjuan WANG; Qi LI; Lixia TANG; Guo ZHANG

doi:10.12449/JCH240516

Volume 40 Issue 5

May 2024

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Effect of the protein kinase RNA-like endoplasmic reticulum kinase pathway in endoplasmic reticulum stress on hepatic stellate cell activation and collagen type I expression

DOI: 10.12449/JCH240516

Fengyan LI^{1, 2},
Zefeng LIU³,
Yuyan XIA²,
Wenjuan WANG³,
Qi LI²,
Lixia TANG²,
Guo ZHANG^{3
,
,
,}

1.
Graduate School，Youjiang Medical University for Nationalities，Bose，Guangxi 533000，China
2.
Department of Gastroenterology，The People’s Hospital of Guangxi Zhuang Autonomous Region，Nanning 530021，China
3.
Department of Gastroenterology，Guangxi Hospital Division of The First Affiliated Hospital，Sun Yat-sen University，Nanning 530022，China

Research funding:

Guangxi Natural Science Foundation Project (2023GXNSFBA026056);

The People’s Hospital of Guangxi Zhuang Autonomous Region Youth Fund project (QN2020-1)

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Corresponding author: ZHANG Guo， zhangguogx@hotmail.com （ORCID： 0000-0001-7755-443X）
Received Date: 2023-10-12
Accepted Date: 2023-11-30
Published Date: 2024-05-25

Abstract

Abstract

Objective To investigate the effect of the protein kinase RNA-like endoplasmic reticulum kinase （PERK）/eukaryotic initiation factor 2α （eIF2α） pathway in endoplasmic reticulum stress on the activation of hepatic stellate cells （HSC）. Methods Pathological sections of normal liver tissue after surgery were collected from 11 patients with hepatic fibrosis （S1-S4） and 9 patients with hepatic hemangioma and hepatic adenoma confirmed by liver biopsy， and immunohistochemistry was used to measure the protein expression levels of PERK， eIF2α， and C/EBP homologous protein （CHOP）. Human HSC-LX2 cells were treated with different concentrations of the endoplasmic reticulum stress inducer thapsigargin （0， 125， 250， 500， and 1 000 nmol/L）， and qRT-PCR was used to measure the mRNA expression level of PERK， while Western blot was used to measure the protein expression levels of PERK， inositol requiring protein 1 （IRE1）， activating transcription factor 6 （ATF6）， CHOP， and α-smooth muscle actin （α-SMA）. The method of lentivirus transfection was used to construct a PERK stable overexpression LX-2 group and a control group； qRT-PCR was used to measure the mRNA expression levels of PERK， eIF2α， and α-SMA， Western blot was used to measure the protein expression levels of PERK， phosphorylated eIF2α （p-eIF2α）， and α-SMA， and immunofluorescence assay was used to measure the expression of collagen type I alpha 1 （COL1A1）. The independent samples t-test was used for comparison of normally distributed continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups. The Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups. Results Compared with normal liver tissue， the liver tissue of patients with hepatic fibrosis had significantly higher expression levels of PERK， eIF2α， and CHOP （Z=-3.56， t=-5.75， Z=-3.52， all P<0.001）. Compared with the solvent group， the groups treated with different concentrations of thapsigargin had significant increases in the expression levels of the endoplasmic reticulum-associated proteins PERK， CHOP， IRE1， ATF6， and α-SMA （all P<0.05）. Compared with the control group， the PERK stable overexpression group had significant increases in the mRNA expression levels of PERK， eIF2α， and α-SMA and the protein expression levels of PERK， p-eIF2α， and α-SMA （all P<0.05）， and immunofluorescence assay showed a significant increase in the expression level of COL1A1 in the PERK stable overexpression group （P<0.05）. Conclusion PERK overexpression can induce the expression of α-SMA and COL1A1 in LX-2 cells， suggesting that the PERK signaling pathway might be one of the important mechanisms of HSC activation.
- Endoplasmic Reticulum Stress,
- Eukaryotic Initiation Factor-2,
- Hepatic Stellate Cells,
- Collagen Type I

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References

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Effect of the protein kinase RNA-like endoplasmic reticulum kinase pathway in endoplasmic reticulum stress on hepatic stellate cell activation and collagen type I expression

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Effect of the protein kinase RNA-like endoplasmic reticulum kinase pathway in endoplasmic reticulum stress on hepatic stellate cell activation and collagen type I expression

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