title: Protein kinase C (PKC) participates in acetaminophen hepatotoxicity through c-jun-N-terminal kinase (JNK)-dependent and -independent signaling pathways.
abstract: 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.
  
  
  CONCLUSIONS
  PKC-α and other PKC(s) regulate death (JNK) and survival (AMPK) proteins, to modulate APAP-induced liver injury.
authors.affiliation: University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9121, USA.
authors.forename: Behnam
authors.initials: B
authors.lastname: Saberi
authors.affiliation: University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9121, USA.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Ybanez
authors.affiliation: University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9121, USA.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Johnson
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92008-7326.
authors.forename: William A
authors.initials: WA
authors.lastname: Gaarde
authors.affiliation: KGI School of Biopharmacy, Keck Graduate Institute, 535 Watson Drive Claremont, CA 91711.
authors.forename: Derick
authors.initials: D
authors.lastname: Han
authors.affiliation: University of Southern California Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089-9121, USA.
authors.forename: Neil
authors.initials: N
authors.lastname: Kaplowitz
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D007211:Indoles; D008301:Maleimides; D047428:Protein Kinase Inhibitors; C071924:Ro 31-8425; D000082:Acetaminophen; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases