Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression

Zhang, Junlin; Singh, Nitesh Kumar; Robinson-Taylor, Kendra S.; Dorsett‐Martin, Wanda; Morris, Michael W.; Earl, Truman M.; Anderson, Christopher

doi:10.1016/j.jss.2015.01.039

Cited by 12 publications

(14 citation statements)

References 27 publications

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“…Most importantly, simultaneous inhibition of autophagy in HCC cells with downregulation of CHOP could partially resensitize ER stress-induced apoptosis. Thus, our data support the notion that CHOP may favor ER stress-induced apoptosis in HCC cells through not only its direct action in regulating pro-apoptotic proteins such as Bcl-2[ 10 , 11 ], but also inhibition of autophagy (summarized in Fig 6 ).…”

Section: Discussionsupporting

confidence: 86%

“…However, the activation of PERK also leads to increased translation of transcription factors such as ATF4, which promote transcription of genes related to cell survival, as well as pro-apoptotic factors such as CHOP (C/EBP homologous protein) [ 7 – 9 ]. CHOP can further downregulate the anti-apoptotic protein Bcl-2 and alter the redox state of the cell [ 10 , 11 ], thus sensitizing cells to apoptosis. Moreover, CHOP also promotes the expression of GADD45 (growth arrest and DNA-damage-inducible protein), triggering cell apoptosis by completely blocking protein synthesis [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy

et al. 2017

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C/EBP-homologous protein (CHOP) is an important component of the endoplasmic reticulum (ER) stress response. We demonstrated the induction of ER stress in response to tunicamycin stimulation, as evidenced by increased expression of chaperone proteins Grp78, Grp94, and enhanced eukaryotic initiation factor 2 subunit 1 (eIF2α) phosphorylation in hepatocellular carcinoma cells. Tunicamycin-induced ER stress resulted in apoptosis and autophagy simultaneously. While inhibition of autophagy mediated by 3-methyladenine pretreatment or direct knockdown of LC3B promoted cell apoptosis, activation of autophagy with rapamycin decreased tunicamycin- induced apoptosis in HCC cells. Furthermore, CHOP was shown to be significantly upregulated upon treatment with tunicamycin in HCC cells. Specific knockdown of CHOP not only enhanced tunicamycin-induced autophagy, but also significantly attenuated ER stress-induced apoptosis in HCC cells. Accordingly, simultaneous inhibition of autophagy in HCC cells with CHOP-knockdown could partially resensitize ER stress-induced apoptosis. Taken together, our data indicate that CHOP may favor ER stress-induced apoptosis in HCC cells via inhibition of autophagy in vitro.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy

et al. 2017

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“…Consistent with the observation that CHOP level remains unchanged, neither Bim nor Bcl2 levels were changed in the VCL testis ( Figure 5(e) ). Normally, in a situation where CHOP is activated, one would expect downward regulation of antiapoptotic Bcl2 and upward regulation of proapoptotic Bim proteins [ 53 ]. None of these events occur in the VCL testis.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic Reticulum Stress (ER Stress) and Unfolded Protein Response (UPR) Occur in a Rat Varicocele Testis Model

Hosseini

Shaygannia

Rahmani

et al. 2020

Oxidative Medicine and Cellular Longevity

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Using a surgically induced varicocele rat model, we show here strong evidence that the misfolded/unfolded protein response that is part of the stress response of the endoplasmic reticulum (ER) is activated in the varicocele testis (VCL), leading to the induction of apoptosis. To support this hypothesis, it is observed that the spliced variant of the X-box protein 1 (XBP1s), resulting from the activation of the inositol-requiring enzyme 1 (IRE1) membrane sensor, is significantly more represented in VCL testicular extracts. The activation of the IRE1/XBP1s pathway is also supported by the observation that the VCL testes show an increase phosphorylation of the c-Jun-kinase (JNK) known to be one intermediate of this pathway and an increased level of caspase-3, the terminal apoptotic effector, partly explaining the apoptotic status of the VCL testis.

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“…Upregulation of the transcription factor CHOP, which has low levels of expression under non-stress conditions, plays a critical role in FFA-mediated ER stress-related liver cell death 48,49 . Treatment of Huh-7 hepatocytes with the FFA palmitate led to increased interaction between CHOP and the other transcription factor c-Jun which bind to the activator protein-1 (AP-1) binding site within the p53 upregulated modulator of apoptosis (PUMA) promoter.…”

Section: Molecular Mechanisms Of Hepatocyte Lipotoxicitymentioning

confidence: 99%

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

et al. 2016

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The exposure of hepatocytes to high concentrations of lipids and carbohydrates and the ensuing hepatocellular injury are termed lipotoxicity and glucotoxicity, respectively. A common denominator is metabolic derangement, especially in regards to intracellular energy homeostasis, which is brought on by glucose intolerance and insulin resistance in tissues. In this review, we highlight the lipids and carbohydrates that provoke hepatocyte injury and the mechanisms involved in lipotoxicity and glucotoxicity, including endoplasmic reticulum stress, oxidative stress and mitochondrial impairment. Through upregulation of proteins involved in various pathways including PKR-like ER kinase (PERK), CCAAT/enhancer-binding homologous protein (CHOP), c-Jun NH2-terminal kinase-1 (JNK), Bcl-2 interacting mediator (BIM), p53 upregulated modulator of apoptosis (PUMA), and eventually caspases, hepatocytes in lipotoxic states ultimately undergo apoptosis. The protective role of certain lipids and possible targets for pharmacological therapy are explored. Finally, we discuss the role of high fructose and glucose diets in contributing to organelle impairment and poor glucose transport mechanisms, which perpetuate hyperglycemia and hyperlipidemia by shunting of excess carbohydrates into lipogenesis.

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Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression

Cited by 12 publications

References 27 publications

CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy

CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy

Endoplasmic Reticulum Stress (ER Stress) and Unfolded Protein Response (UPR) Occur in a Rat Varicocele Testis Model

Molecular mechanisms of lipotoxicity and glucotoxicity in nonalcoholic fatty liver disease

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