Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through c-jun-N-terminal kinase (JNK)-dependent and -independent signaling pathways
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UNLABELLED: This study examines the role of protein kinase C (PKC) and AMP-activated kinase (AMPK) in acetaminophen (APAP) hepatotoxicity. Treatment of primary mouse hepatocytes with broad-spectrum PKC inhibitors (Ro-31-8245, Go6983), protected against APAP cytotoxicity despite sustained c-jun-N-terminal kinase (JNK) activation. Broad-spectrum PKC inhibitor treatment enhanced p-AMPK levels and AMPK regulated survival-energy pathways including autophagy. AMPK inhibition by compound C or activation using an AMPK activator oppositely modulated APAP cytotoxicity, suggesting that p-AMPK and AMPK regulated energy survival pathways, particularly autophagy, play a critical role in APAP cytotoxicity. Ro-31-8245 treatment in mice up-regulated p-AMPK levels, increased autophagy (i.e., increased LC3-II formation, p62 degradation), and protected against APAP-induced liver injury, even in the presence of sustained JNK activation and translocation to mitochondria. In contrast, treatment of hepatocytes with a classical PKC inhibitor (Go6976) protected against APAP by inhibiting JNK activation. Knockdown of PKC-α using antisense (ASO) in mice also protected against APAP-induced liver injury by inhibiting JNK activation. APAP treatment resulted in PKC-α translocation to mitochondria and phosphorylation of mitochondrial PKC substrates. JNK 1 and 2 silencing in vivo decreased APAP-induced PKC-α translocation to mitochondria, suggesting PKC-α and JNK interplay in a feed-forward mechanism to mediate APAP-induced liver injury. CONCLUSION: PKC-α and other PKC(s) regulate death (JNK) and survival (AMPK) proteins, to modulate APAP-induced liver injury.
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AMPK can be suppressed by alcohol or other agents such as high fat diet and APAP.
“In contrast, AMPK can be suppressed by alcohol [137] or other agents such as high fat diet [138] and APAP [139].”
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Song, B.-J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., & Hardwick, J. P. (2014) · Redox Biology · doi:10.1016/j.redox.2014.10.004 · Cited by 123 · see citing works
- Authors
- Saberi, B., Ybanez, M. D., Johnson, H. S., Gaarde, W. A., Han, D., & Kaplowitz, N.
- Affiliations
- University of Southern California (US)
- Ionis Pharmaceuticals (United States) (US)
- Keck Graduate Institute (US)
- Corresponding author
- Kaplowitz, Neil
- Venue
- Hepatology
- Published
- 2014-04
- Volume
- 59
- Issue
- 4
- Pages
- 1543-1554
- ISSN
- 0270-9139 (ISSN-L)
- PMC
- PMC3997165
- OpenAlex
- W1576016712
- Cited by
- 88
- References
- 34
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 2 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 8 · 2018: 17 · 2017: 8 · 2016: 6 · 2015: 15 · 2014: 7 · 2013: 2
- FWCI
- 10.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Hepatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1s10rr022508-01a1)
- University of California, San Francisco
- National Institute on Alcohol Abuse and Alcoholism (K01AA016911, AA016911)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK067215, DK067215, P30DK048522)
- National Center for Research Resources (S10-RR022508)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
- Keywords
- protein kinase C, acetaminophen hepatotoxicity, c-Jun N-terminal kinase, AMPK, protein kinase C alpha, autophagy, mitochondrial translocation, hepatocyte death, liver injury, JNK signaling, energy metabolism, PKC inhibitors
- MeSH terms
- Acetaminophen, Animals, Cells, Cultured, Disease Models, Animal, Indoles, Male, Maleimides, Mice, Inbred C57BL, Mitochondria, Liver, Necrosis, Protein Kinase C, Signal Transduction, Hepatocytes, Protein Kinase Inhibitors, JNK Mitogen-Activated Protein Kinases, Mice, AMP-Activated Protein Kinases, Chemical and Drug Induced Liver Injury, In Vitro Techniques
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