HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 295/1/C50    most recent 90654.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Saberi, B. Articles by Han, D. Search for Related Content PubMed PubMed Citation Articles by Saberi, B. Articles by Han, D.

GROWTH, DIFFERENTIATION, AND APOPTOSIS

Regulation of H₂O₂-induced necrosis by PKC and AMP-activated kinase signaling in primary cultured hepatocytes

¹Research Center for Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles; and ²Isis Pharmaceuticals, Carlsbad, California

Submitted 27 December 2007 ; accepted in final form 30 April 2008

Recent studies have suggested that, in certain cases, necrosis, like apoptosis, may be programmed, involving the activation and inhibition of many signaling pathways. In this study, we examined whether necrosis induced by H₂O₂ is regulated by signaling pathways in primary hepatocytes. A detailed time course revealed that H₂O₂ treated to hepatocytes is consumed within minutes, but hepatocytes undergo necrosis several hours later. Thus, H₂O₂ treatment induces a "lag phase" where signaling changes occur, including PKC activation, Akt (PKB) downregulation, activation of JNK, and downregulation of AMP-activated kinase (AMPK). Investigation of various inhibitors demonstrated that PKC inhibitors were effective in reducing necrosis caused by H₂O₂ (80%). PKC inhibitor treatment decreased PKC activity but, surprisingly, also upregulated Akt and AMPK, suggesting that various PKC isoforms negatively regulate Akt and AMPK. Akt did not appear to play a significant role in H₂O₂-induced necrosis, since PKC inhibitor treatment protected hepatocytes from H₂O₂ even when Akt was inhibited. On the other hand, compound C, a selective AMPK inhibitor, abrogated the protective effect of PKC inhibitors against necrosis induced by H₂O₂. Furthermore, AMPK activators protected against H₂O₂-induced necrosis, suggesting that much of the protective effect of PKC inhibition was mediated through the upregulation of AMPK. Work with PKC inhibitors suggested that atypical PKC downregulates AMPK in response to H₂O₂. Knockdown of PKC- using antisense oligonucleotides also slightly protected (22%) against H₂O₂. Taken together, our data demonstrate that the modulation of signaling pathways involving PKC and AMPK can alter H₂O₂-induced necrosis, suggesting that a signaling "program" is important in mediating H₂O₂-induced necrosis in primary hepatocytes.

necrosis; protein kinase C; AMP-activated kinase; hydrogen peroxide; Akt

This article has been cited by other articles:

				J.-Y. Hong, M. Lebofsky, A. Farhood, and H. Jaeschke Oxidant stress-induced liver injury in vivo: role of apoptosis, oncotic necrosis, and c-Jun NH2-terminal kinase activation Am J Physiol Gastrointest Liver Physiol, March 1, 2009; 296(3): G572 - G581. [Abstract] [Full Text] [PDF]