Ethanol induces apoptosis in hepatocytes by a pathway involving novel protein kinase C isoforms

Yanhong Zhang, Senthil K. Venugopal, Songqing He, Pingguo Liu, Jian Wu, Mark A Zern

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Ethanol abuse is one of the major etiologies of cirrhosis. Ethanol has been shown to induce apoptosis via activation of oxidative stress, mitogen-activated protein kinases (MAPK), and tyrosine kinases. However, there is a paucity of data that examine the interplay among these molecules. In the present study we have systematically elucidated the role of novel protein kinase C isoforms (nPKC; PKCδ and PKCe{open}) in ethanol-induced apoptosis in hepatocytes. Ethanol enhanced membrane translocation of PKCδ and PKCe{open}, which was associated with the phosphorylation of p38MAPK, p42/44MAPK and JNK1/2, and the nuclear translocation of NF-κB and AP-1. This resulted in increased apoptosis in primary rat hepatocytes. Inhibition of both PKCδ and PKCe{open} resulted in a decreased MAPK activation, decreased nuclear translocation of NF-κB and AP-1, and inhibition of apoptosis. In addition, ethanol activated the tyrosine phosphorylation of PKCδ via tyrosine kinase in hepatocytes. The tyrosine phosphorylated PKCδ was cleaved by caspase-3 and these fragments were translocated to the nucleus. Inhibition of ethanol-induced oxidative stress blocked the membrane translocation of PKCδ and PKCe{open}, and the tyrosine phosphorylation of PKCδ in hepatocytes. Inhibition of oxidative stress, tyrosine kinase or caspase-3 activity caused a decreased nuclear translocation of PKCδ in response to ethanol, and was associated with less apoptosis. Conclusion: These results provide a newly-described mechanism by which ethanol induces apoptosis via activation of nPKC isoforms in hepatocytes.

Original languageEnglish (US)
Pages (from-to)2339-2350
Number of pages12
JournalCellular Signalling
Volume19
Issue number11
DOIs
StatePublished - Nov 2007

Keywords

  • Apoptosis
  • Mitogen-activated protein kinase
  • Oxidative stress
  • Phosphorylation
  • Primary rat hepatocytes
  • Protein kinase C
  • Translocation

ASJC Scopus subject areas

  • Cell Biology

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