Activation and Dysregulation of the Unfolded Protein Response in Nonalcoholic Fatty Liver Disease

Puri, Puneet; Mirshahi, Faridoddin; Cheung, Onpan; Natarajan, Ramesh; Maher, James W.; Kellum, John M.; Sanyal, Arun J.

doi:10.1053/j.gastro.2007.10.039

Cited by 530 publications

(433 citation statements)

References 35 publications

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“…This discordant induction of the ISR was also reported in brain ischemia and non-alcoholic steatohepatitis (26,27). Along with preferential translation of ATF4, transcriptional induction of ATF4 is a contributor to its increased expression in the ISR (25,28,29).…”

supporting

confidence: 62%

“…In addition to UV irradiation for which we showed that LIP represses ATF4 transcription, brain ischemia and Non-alcoholic steatohepatitis were reported to induce eIF2␣ϳP yet trigger low ATF4 expression (Fig. 10B) (26,27). Therefore, ATF4 repression in the ISR is suggested to be important among different physiological stresses.…”

Section: Transcriptional Regulation Combined With Translational Contrmentioning

confidence: 89%

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Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

Dey

Savant

Teske

et al. 2012

Journal of Biological Chemistry

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Background: eIF2ϳP induces translational expression of ATF4, an ISR transcription factor that regulates cell survival during stress. Results: The LIP isoform of C/EBP␤ represses ATF4 transcription during UV stress, reducing ATF4 mRNA available for preferential translation by eIF2ϳP. Conclusion: Transcription of ATF4 is controlled by different stress signaling pathways. Significance: Differential ISR expression during eIF2ϳP is important for alleviation of cell damage during environmental stresses.

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supporting

confidence: 62%

Section: Transcriptional Regulation Combined With Translational Contrmentioning

confidence: 89%

Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

Dey

Savant

Teske

et al. 2012

Journal of Biological Chemistry

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“…Whole-cell lysates were prepared as previously described. 9 Equal amounts of protein (20-50 mg) was resolved by SDS-PAGE on a 4-12% NuPAGE Novex Bis-Tris Mini Gels (Invitrogen), then transferred to nitrocellulose membranes and incubated with primary antibodies. Membranes were incubated with appropriate horseradish peroxidase-conjugated secondary antibodies (Cell Signaling Technology, Danvers, MA, USA).…”

Section: Discussionmentioning

confidence: 99%

“…Quantification of the complementary DNA template was performed by real-time PCR using SYBR green fluorescence on a CFX96 Real-Time PCR Detection System (Bio-Rad, Hercules, CA, USA) as described before by us in detail. 9 LC3 immunofluorescence analysis. GFP-LC3 lentiviral particles have been described previously.…”

Section: Discussionmentioning

confidence: 99%

“…5,8 Given this information, it is not surprising that JNK is activated in both human NASH 5,9 and in dietary murine models of NASH. [10][11][12] Hepatocytes express two JNK genes, Jnk1 and Jnk2; and although both isoforms have been implicated in liver injury, 10,13 JNK1 signaling has a central role in inducing hepatocyte apoptosis in in vivo 10 and in vitro model of steatohepatitis.…”

mentioning

confidence: 99%

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Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

et al. 2014

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Non-alcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA) and hepatocyte lipoapoptosis. This lipoapoptosis requires increased JNK phosphorylation and activation of the pro-apoptotic BH3-only proteins Bim and PUMA. Kelch-like ECH-associated protein (Keap)-1 is a BTB/Kelch protein that can regulate the expression of Bcl-2 protein and control apoptotic cell death. Yet, the role of Keap1 in hepatocyte lipotoxicity is unclear. Here we demonstrate that Keap1 protein was rapidly degraded in hepatocytes, through autophagy in a p62-dependent manner, in response to the toxic saturated FFA palmitate, but not following incubation with the non-toxic FFA oleic acid. Stable knockdown of Keap1 expression, using shRNA technology, in hepatocarcinoma cell lines induced spontaneous cell toxicity that was associated with JNK1-dependent upregulation of Bim and PUMA protein levels. Also, Keap1 knockdown further sensitized hepatocytes to lipoapoptosis by palmitate. Likewise, primary hepatocytes isolated from liver-specific Keap1 À / À mice displayed higher Bim and PUMA protein levels and demonstrated increased sensitivity to palmitate-induced apoptosis than wild-type mouse hepatocytes. Finally, stable knockdown of Bim or PUMA expression prevented cell toxicity induced by loss of Keap1. These results implicate p62-dependent autophagic degradation of Keap1 by palmitate as a mechanism contributing to hepatocyte lipoapoptosis.

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MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives

Karin,

Kim

2024

Molecular Oncology

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Hepatocellular carcinoma is one of the deadliest and fastest‐growing cancers. Among HCC etiologies, metabolic dysfunction‐associated fatty liver disease (MAFLD) has served as a major HCC driver due to its great potential for increasing cirrhosis. The obesogenic environment fosters a positive energy balance and results in a continuous rise of obesity and metabolic syndrome. However, it is difficult to understand how metabolic complications lead to the poor prognosis of liver diseases and which molecular mechanisms are underpinning MAFLD‐driven HCC development. Thus, suitable preclinical models that recapitulate human etiologies are essentially required. Numerous preclinical models have been created but not many mimicked anthropometric measures and the course of disease progression shown in the patients. Here we review the literature on adipose tissues, liver‐related HCC etiologies and recently discovered genetic mutation signatures found in MAFLD‐driven HCC patients. We also critically review current rodent models suggested for MAFLD‐driven HCC study.

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Activation and Dysregulation of the Unfolded Protein Response in Nonalcoholic Fatty Liver Disease

Cited by 530 publications

References 35 publications

Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

Transcriptional Repression of ATF4 Gene by CCAAT/Enhancer-binding Protein β (C/EBPβ) Differentially Regulates Integrated Stress Response

Degradation of Keap1 activates BH3-only proteins Bim and PUMA during hepatocyte lipoapoptosis

MASH as an emerging cause of hepatocellular carcinoma: current knowledge and future perspectives

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