Elucidation of the mechanism of NEFA-induced PERK-eIF2α signaling pathway regulation of lipid metabolism in bovine hepatocytes

Huang, Yan; Zhao, Chenxu; Kong, Yezi; Tan, Panpan; Liu, Siqi; Liu, Yaoquan; Zeng, Fangyuan; Yuan, Yang; Zhao, Bin; Wang, Jianguo

doi:10.1016/j.jsbmb.2021.105893

Cited by 18 publications

(17 citation statements)

References 43 publications

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“…In eukaryotic cells, protein kinase RNA-like ER kinase (PERK), inositol requiring enzyme-1α (IRE1α), and activating transcription factor-6α (ATF6α) were divided from the molecular chaperone GRP78 in ER stress, permitting transduction of downstream signals and initiating the expression of CHOP. The overexpression of CHOP plays a critical role in the process of apoptosis ( Rao et al, 2015 ; Huang et al, 2021 ). Meanwhile, more and more researchers are focusing on the diseases caused by ER stress and suggest that ER stress could mediate other factors to induce liver injury ( Iracheta-Vellve et al, 2016 ; Han et al, 2018 ; Torres et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

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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Section: Introductionmentioning

confidence: 99%

CHOP Regulates Endoplasmic Reticulum Stress-Mediated Hepatoxicity Induced by Monocrotaline

et al. 2021

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“…The content of lipids is primarily determined by a combination of lipid biosynthesis and decomposition. In our previous study, the NEFA-induced PERK signaling pathway was shown to be involved in enhanced lipid oxidation, which can effectively alleviate the lipotoxicity caused by NEFA [ 6 ]. Moreover, an increasing focus has been placed on the role of autophagy in liver steatosis because autophagy can effectively mediate lipid degradation [ 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…The hepatocytes were then cultured for 5 h at 37 °C and 5% CO 2 . The NEFA stock (52.7 mM) solution was prepared as previously described [ 6 ].…”

Section: Methodsmentioning

confidence: 99%

“…It has been shown that NEFA-induced lipotoxicity can elicit several stress-related responses, such as endoplasmic reticulum (ER) stress and oxidative stress [ 5 , 6 , 7 ]. The perturbations in ER homeostasis can lead to increased accumulation of unfolded or misfolded proteins in the ER during cellular stress, which is collectively termed ER stress.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, when the liver is exposed to a high blood concentration of NEFA, autophagy plays an important role in maintaining the stability of hepatocytes, thereby providing nutrients and alleviating lipid accumulation. Our previous study showed that NEFA can activate the PERK-eIF2α signaling pathway to regulate lipid metabolism in hepatocytes [ 6 ]. However, it is unclear whether NEFA could mediate the activation of the PERK-eIF2α signaling pathway to affect hepatic autophagy in dairy cows.…”

Section: Introductionmentioning

confidence: 99%

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NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes

Huang

Zhao

Liu

et al. 2021

Animals

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During the perinatal period, the abnormally high plasma non-esterified fatty acids (NEFA) concentration caused by the negative energy balance (NEB) can impose a significant metabolic stress on the liver of dairy cows. Endoplasmic reticulum (ER) stress is an important adaptive response that can serve to maintain cell homeostasis in the event of stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) pathway is the most rapidly activated cascade when ER stress occurs in cells and has an important impact on the regulation of hepatic lipid metabolism and autophagy modulation. However, it is unknown whether NEFA can affect autophagy through modulating the PERK pathway, under NEB conditions. In this study, we provide evidence that NEFA treatment markedly increased lipid accumulation, the phosphorylation level of PERK and eukaryotic initiation factor 2α (eIF2α), and the expression of glucose-regulated protein 78 (Grp78), activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). More importantly, NEFA treatment can cause a substantial increase in the protein levels of autophagy-related gene 7 (ATG7), Beclin-1 (BECN1), sequestosome-1 (p62), and microtubule-associated protein 1 light chain 3 (LC3)-II, and in the number of autophagosomes in primary bovine hepatocytes. The addition of GSK2656157 (PERK phosphorylation inhibitor) can significantly inhibit the effect of NEFA on autophagy and can further increase lipid accumulation. Overall, our results indicate that NEFA could promote autophagy via the PERK pathway in bovine hepatocytes. These findings provide novel evidence about the potential role of the PERK signaling pathway in maintaining bovine hepatocyte homeostasis.

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Deoxynivalenol and T-2 toxin cause liver damage and egg quality degradation through endoplasmic reticulum stress in summer laying hens

Guo,

Wan,

Lou

et al. 2024

Int J Biometeorol

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The present study aimed to nd whether low doses of mixed mycotoxins would affect egg quality in laying hens, and to explore the oxidative stress induced liver damage through endoplasmic reticulum during summer stress. A total of 96 Jinghong laying hens, 36 wks of age, were divided into four treatments, with eight repetitions per treatment and three hens per repetition. All the hens were raised in summer (average temperature: 31.3 ± 0.5℃; average humidity: 85.5 ± 0.2%) for 28d. One treatment was fed a basal diet as control (CON), and the other three treatments were fed the same diets containing 3.0 mg/kg deoxynivalenol (DON), 0.5 mg/kg T-2 toxin (T-2), and 1.5 mg/kg DON + 0.25 mg/kg T-2 toxin (Mix). Albumen height and Haugh unit were decreased (P < 0.05) in the Mix group on day 14 and 28. The activity of total antioxidant capacity, glutathione peroxidase, catalase, and superoxide dismutase were decreased (P < 0.05) in the DON, T-2, and Mix groups. The alkaline phosphatase level in DON, T-2, and Mix groups was signi cantly increased (P < 0.05). The level of interleukin-1β, interferon-γ, and tumor necrosis factor-α in the Mix group were higher (P < 0.05) than CON, DON, and T-2 groups. Mix group upregulated the mRNA expressions of protein kinase RNA-like ER kinase, activating transcription factor4, IL-1β, nuclear factor-κgene binding, and nuclear respiratory factor 2 in the liver (P < 0.05). The results showed that low doses of DON and T-2 toxin could cause oxidative stress in the liver, but DON and T-2 toxin have a cumulative effect on virulence, which can reduce egg quality and cause endoplasmic reticulum stress in the liver.

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Elucidation of the mechanism of NEFA-induced PERK-eIF2α signaling pathway regulation of lipid metabolism in bovine hepatocytes

Cited by 18 publications

References 43 publications

CHOP Regulates Endoplasmic Reticulum Stress-Mediated Hepatoxicity Induced by Monocrotaline

CHOP Regulates Endoplasmic Reticulum Stress-Mediated Hepatoxicity Induced by Monocrotaline

NEFA Promotes Autophagosome Formation through Modulating PERK Signaling Pathway in Bovine Hepatocytes

Deoxynivalenol and T-2 toxin cause liver damage and egg quality degradation through endoplasmic reticulum stress in summer laying hens

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