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

Guo, Yazhou; Guo, Rong; Su, Yongxia; Fu, Jingjing; Wang, Shuai; Kong, Yezi; Wu, Chenchen; Wang, Jianguo; Tan, Carol; Mo, Chonghui; Zhao, Bin

doi:10.1016/j.rvsc.2020.03.021

Cited by 25 publications

(10 citation statements)

References 24 publications

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“…3a), which was more severe than in myotubes treated with the well-known ER stress inducer, palmitate. PERK-eIF2α regulates cell death via ATF4 and CHOP activation upon ER stress 24 , and inhibits protein synthesis via the 43S preinitiation complex 25 . We excluded a possibility that FABP3 induced cell death via PERK-eIF2α, because FABP3 expression did not induce Atf4 and Chop mRNA expression ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging

Lee

Jung

et al. 2020

Nat Commun

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Sarcopenia is characterized by decreased skeletal muscle mass and function with age. Aged muscles have altered lipid compositions; however, the role and regulation of lipids are unknown. Here we report that FABP3 is upregulated in aged skeletal muscles, disrupting homeostasis via lipid remodeling. Lipidomic analyses reveal that FABP3 overexpression in young muscles alters the membrane lipid composition to that of aged muscle by decreasing polyunsaturated phospholipid acyl chains, while increasing sphingomyelin and lysophosphatidylcholine. FABP3-dependent membrane lipid remodeling causes ER stress via the PERK-eIF2α pathway and inhibits protein synthesis, limiting muscle recovery after immobilization. FABP3 knockdown induces a young-like lipid composition in aged muscles, reduces ER stress, and improves protein synthesis and muscle recovery. Further, FABP3 reduces membrane fluidity and knockdown increases fluidity in vitro, potentially causing ER stress. Therefore, FABP3 drives membrane lipid composition-mediated ER stress to regulate muscle homeostasis during aging and is a valuable target for sarcopenia.

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Section: Resultsmentioning

confidence: 99%

FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging

Lee

Jung

et al. 2020

Nat Commun

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“…As a major pathological cellular process, MCT-induced apoptosis has been found in the liver ( Nakamura et al, 2012 ). Meanwhile, our previous study suggested that MCT could induce ER stress in liver ( Guo et al, 2020 ). However, the interplay between apoptosis and ER stress in MCT-induced pathological processes is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…While our previous study suggested that MCT could induce ER stress in rat livers ( Guo et al, 2020 ), it is not known whether ER stress participates in MCT-induced hepatocyte apoptosis as well. In this study, we confirmed that ER stress was involved in MCT-induced hepatotoxicity.…”

Section: Introductionmentioning

confidence: 89%

CHOP Regulates Endoplasmic Reticulum Stress-Mediated Hepatoxicity Induced by Monocrotaline

et al. 2021

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Monocrotaline (MCT), a pyrrolizidine alkaloid, is the major toxin in Crotalaria, which causes cell apoptosis in humans and animals. It has been reported that the liver is a vulnerable target of MCT. However, the exact molecular mechanism of the interaction between endoplasmic reticulum (ER) stress and liver injury induced by MCT is still unclear. In this study, the cytotoxicity of MCT on primary rat hepatocytes was analyzed by a CCK-8 assay and Annexin V-FITC/PI assay. Protein expression was detected by western blotting and immunofluorescence staining. As a result, MCT significantly decreased the cell viability and mediated the apoptosis of primary rat hepatocytes. Meanwhile, MCT could also induce ER stress in hepatocytes, indicated by the expression of ER stress-related proteins, including GRP78, p-IRE1α, ATF6, p-eIF2α, ATF4, and CHOP. Pretreatment with 4-PBA, an inhibitor of ER stress, or knockdown of CHOP by siRNA could partly enhance cell viability and relieve the apoptosis. Our findings indicate that ER stress is involved in the hepatotoxicity induced by MCT, and CHOP plays an important role in this process.

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“…3A and 3F), indicating that the exposure of AECIIs to 95 % oxygen increased the expression of CHOP, a major pro-apoptotic transcription factor induced by ER stress. PERK and ATF6 were ERS sensors, ATF4 were their downstream-activated proteins that activated CHOP expression according to the previously reported mechanism [21][22][23]. As shown in Fig.…”

Section: Effects Of Hyperoxia On Grp-78 Chop and Ers Sensors Expressionmentioning

confidence: 65%

The Function Role of Ubiquitin Proteasome Pathway in the ER Stress-induced AECII Apoptosis during Hyperoxia Exposure

Zhu

et al. 2021

Preprint

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Backgroud: Bronchopulmonary dysplasia (BPD) is a major cause of mortality and morbidity in premature infants, characterized by alveolar dysplasia and pulmonary microvascular remodeling. In the present study, we have investigated the functional roles of ubiquitin proteasome pathway (UPP) in BPD, and its relationship with endoplasmic reticulum stress (ER stress, ERS) mediated AECII apoptosis. Methods: A hyperoxia-induced BPD rat model was constructed and the pathologic changes of lung tissues were evaluated by Hematoxylin-Eosin staining. Cell apoptosis and protein expression were determined by TUNEL assay and Western blotting, respectively. Further reagent kit with specific fluorescent substrate was utilized to measure the activity of 20s proteasome. Meanwhile, AECII were cultured in vitro and exposed to hyperoxia. AECII apoptosis were measured by flow cytometry. In contrast, MG132 treatment was induced to explore ubiquitin proteasome pathway during hyperoxia exposure on AECII apoptosis and ERS sensors expression.Results: A significant increase in apoptosis and total ubiquitinated proteins expression were observed in BPD rats and AECII culture, and the change of UPP was associated with ERS. In order to confirm the role of UPP in AECII apoptosis of BPD, AECII cells were treated by MG132 with the concentration of 10 μmol/L under hyperoxia exposure. We found that the proteins expression of GRP-78, PERK, ATF4, ATF6 and CHOP, as well as AECII apoptosis were increased following MG132 treatment. Furthermore, the relatively up-regulated in the levels of total ubiquitinated proteins expression and 20S proteasome activity were correlated with increased ERS sensors expression. Conclusions: Our findings indicate that UPP may participate in the ERS-induced AECII apoptosis under hyperoxia condition.

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

Cited by 25 publications

References 24 publications

FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging

FABP3-mediated membrane lipid saturation alters fluidity and induces ER stress in skeletal muscle with aging

CHOP Regulates Endoplasmic Reticulum Stress-Mediated Hepatoxicity Induced by Monocrotaline

The Function Role of Ubiquitin Proteasome Pathway in the ER Stress-induced AECII Apoptosis during Hyperoxia Exposure

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