Silencing Glycogen Synthase Kinase-3β Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1

Shinohara, Mie; Ybanez, Maria D.; Win, Sanda; Than, Tin Aung; Jain, Shilpa; Gaarde, William A.; Han, Derick; Kaplowitz, Neil

doi:10.1074/jbc.m109.054999

Cited by 108 publications

(111 citation statements)

References 52 publications

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“…This discrepancy could be due to several possibilities. First, in this study, we used fed mice to avoid the possible interference of starvation-induced autophagy, whereas Shinohara et al (29) used starved animals. Starvation may inactivate AKT and interfere with AKT-GSK3␤-mediated Mcl-1 phosphorylation and proteasomal degradation.…”

Section: Mcl-1 Expression Was Differentially Regulated In Parkin Ko Omentioning

confidence: 99%

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Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice

Williams

Haynes

et al. 2015

Journal of Biological Chemistry

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Background: Parkin is required for mitophagy in cultured cells, but its role in liver injury is not known. Results: APAP-induced mitophagy was impaired in acute Parkin knockdown mouse livers but not whole body Parkin knock-out mice. Conclusion: Chronic, but not acute, loss of Parkin protects against APAP-induced liver injury by multiple mechanisms independent of mitophagy. Significance: This study revealed a novel role of Parkin in APAP-induced liver injury.

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Section: Mcl-1 Expression Was Differentially Regulated In Parkin Ko Omentioning

confidence: 99%

“…Mcl-1 is an anti-apoptotic protein that has been shown to be protective against APAP-induced liver injury (28,29). We measured protein levels of Mcl-1 using total lysate from WT and Parkin KO mouse livers 6 h after APAP treatment.…”

Section: Parkin Ko Mice Had Decreased Jnk Activation and Increased MCmentioning

confidence: 99%

Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice

Williams

Haynes

et al. 2015

Journal of Biological Chemistry

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“…1 Acetaminophen (APAP) is the leading offender in causing ALF; however, despite extensive work, mechanisms of DILI by APAP are incompletely understood. [2][3][4][5] The identification of molecular pathways initiating or amplifying DILI will be highly significant for drug development and for preventing and/or treating ALF. After exposure to hepatotoxic drugs, perturbations in cell stress and toxicity pathways assume prominence.…”

mentioning

confidence: 99%

“…Previously, these intracellular cell signaling and hepatocellular growth-arrest mechanisms had not been identified in DILI. [2][3][4][5] Recapitulation of multiple aspects of ALF in humans, including mortality several days after DILI, permitted us to examine therapeutic mechanisms. This was important because mortality in people with ALF remains extremely high (ie, 50%-70%).…”

mentioning

confidence: 99%

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Bandi

Joseph

Berishvili

et al. 2011

The American Journal of Pathology

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Superior insights into molecular mechanisms of liver failure, which are not fully understood, will help strategies for inducing liver regeneration. We examined hepatotoxic mechanisms in mice homozygous for the severe combined immune deficiency mutation in the protein kinase, DNA-activated, catalytic polypeptide. Mice were treated with rifampicin, phenytoin, and monocrotaline. The ensuing acute liver failure was characterized by serological, histological, and mRNA studies. Subsequently, we studied whether transplantation of hepatocytes could rescue animals with liver failure. We found extensive liver damage in these animals, with mortality over several days. The expression of multiple hepatic genes was rapidly altered, including those representing pathways in oxidative/metabolic stress, inflammation, DNA damage-repair, and ataxia telangiectasia mutant (Atm) signaling pathways. This led to liver cell growth arrest involving cyclin-dependent kinase inhibitor 1A. Transplantation of hepatocytes with microcarriers in the peritoneal cavity efficiently rescued animals with liver failure. Molecular abnormalities rapidly reversed, including in hepatic Atm and downstream signaling pathways; and residual hepatocytes overcame cyclin-dependent kinase inhibitor 1A-induced cell growth arrest. Reseeding of the liver with transplanted hepatocytes was not required for rescue because native hepatocytes overcame cell growth-arrest to regenerate the liver. This likely resulted from paracrine signaling from hepatocytes in the peritoneal cavity. We concluded that Atm signaling Drug-induced liver injury (DILI) often results in acute liver failure (ALF). 1 Acetaminophen (APAP) is the leading offender in causing ALF; however, despite extensive work, mechanisms of DILI by APAP are incompletely understood. [2][3][4][5] The identification of molecular pathways initiating or amplifying DILI will be highly significant for drug development and for preventing and/or treating ALF. After exposure to hepatotoxic drugs, perturbations in cell stress and toxicity pathways assume prominence. However, more information is required regarding intracellular signaling pathways that impart susceptibility to DILI. Similarly, more information is required regarding failure of liver regeneration in ALF. Nevertheless, establishing these mechanisms has been difficult in the available animal models of ALF. For instance, after exposure to toxic drugs or chemicals, some animals may exhibit rapid and irreversible mortality (eg, within 24 -30 hours after APAP), whereas other animals may recover spontaneously.

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“…In addition to JNK, other cytosolic proteins such as Bax also undergo translocation to mitochondria early after APAP overdose in mice [51, 52], though this does not seem to influence mitochondrial oxidant stress and peroxynitrite formation [51], but may be directly involved in regulation of subsequent alterations such as the mitochondrial permeability transition, detailed below. In addition to JNK and Bax, translocation of cytosolic glycogen synthase kinase-3β (GSK-3β), a major regulator of glycogen synthase, to mitochondria has also been shown early after APAP overdose, and silencing GSK-3β protected against APAP hepatotoxicity in vivo [53]. Inhibition of GSK 3 also accelerated liver regeneration after APAP overdose in mice [54].…”

Section: Acetaminophen Hepatotoxicitymentioning

confidence: 99%

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

et al. 2018

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Mitochondria are critical cellular organelles for energy generation and are now also recognized as playing important roles in cellular signaling. Their central role in energy metabolism, as well as their high abundance in hepatocytes, make them important targets for drug-induced hepatotoxicity. This review summarizes the current mechanistic understanding of the role of mitochondria in drug-induced hepatotoxicity caused by acetaminophen, diclofenac, anti-tuberculosis drugs such as rifampin and isoniazid, anti-epileptic drugs such as valproic acid and constituents of herbal supplements such as pyrrolizidine alkaloids. The utilization of circulating mitochondrial-specific biomarkers in understanding mechanisms of toxicity in humans will also be examined. In summary, it is well-established that mitochondria are central to acetaminophen-induced cell death. However, the most promising areas for clinically useful therapeutic interventions after acetaminophen toxicity may involve the promotion of adaptive responses and repair processes including mitophagy and mitochondrial biogenesis, In contrast, the limited understanding of the role of mitochondria in various aspects of hepatotoxicity by most other drugs and herbs requires more detailed mechanistic investigations in both animals and humans. Development of clinically relevant animal models and more translational studies using mechanistic biomarkers are critical for progress in this area.

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Silencing Glycogen Synthase Kinase-3β Inhibits Acetaminophen Hepatotoxicity and Attenuates JNK Activation and Loss of Glutamate Cysteine Ligase and Myeloid Cell Leukemia Sequence 1

Cited by 108 publications

References 52 publications

Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice

Chronic Deletion and Acute Knockdown of Parkin Have Differential Responses to Acetaminophen-induced Mitophagy and Liver Injury in Mice

Perturbations in Ataxia Telangiectasia Mutant Signaling Pathways After Drug-Induced Acute Liver Failure and Their Reversal During Rescue of Animals by Cell Therapy

Mitochondrial dysfunction as a mechanism of drug-induced hepatotoxicity: current understanding and future perspectives

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