Suppression of Fas-mediated signaling pathway is involved in zinc inhibition of ethanol-induced liver apoptosis

Jason C. Lambert, Zhanxiang Zhou, Yujian Kang

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Apoptosis is critically involved in hepatic pathogenesis induced by acute alcohol exposure. This study was undertaken to test the hypothesis that zinc interferes with an important Fas ligand-mediated pathway in the liver, leading to the inhibition of ethanol-induced apoptosis. Male 129/SvPCJ mice were injected subcutaneously with ZnSO4 (5 mg of Zn ion/kg) in 12-hr intervals for 24 hr before intragastric administration of ethanol (5 g/kg) in 12-hr intervals for 36 hr. Ethanol-induced apoptosis in the liver was detected by a terminal deoxynucleotidyl transferase nick-end labeling assay and was further confirmed by electron microscopy. The number of apoptotic cells in the livers pretreated with zinc was significantly decreased, being only 15% of that found in the animals treated with ethanol only. Characteristic apoptotic morphological changes observed by electron microscopy were also inhibited by zinc. Importantly, zinc inhibited ethanol-induced activation of caspase-3, the primary executioner protease responsible for alcohol-induced liver apoptosis, and caspase-8 as determined by enzymatic assay. Immunohistochemical analysis revealed that zinc inhibited ethanol-induced endogenous Fas ligand activation, which is a key component in signaling pathways leading to hepatic caspase-8 and subsequent caspase-3 activation and apoptosis. These results demonstrate that zinc is a potent inhibitor of acute ethanol-induced liver apoptosis, and this effect occurs primarily through zinc interference with Fas ligand pathway and the suppression of caspase-3.

Original languageEnglish (US)
Pages (from-to)406-412
Number of pages7
JournalExperimental Biology and Medicine
Volume228
Issue number4
DOIs
StatePublished - Jan 1 2003
Externally publishedYes

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Liver
Zinc
Ethanol
Apoptosis
Fas Ligand Protein
Caspase 3
Caspase 8
Chemical activation
Electron microscopy
Assays
Electron Microscopy
Alcohols
129 Strain Mouse
DNA Nucleotidylexotransferase
Enzyme Assays
Labeling
Animals
Peptide Hydrolases
Cell Count
Cells

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Suppression of Fas-mediated signaling pathway is involved in zinc inhibition of ethanol-induced liver apoptosis. / Lambert, Jason C.; Zhou, Zhanxiang; Kang, Yujian.

In: Experimental Biology and Medicine, Vol. 228, No. 4, 01.01.2003, p. 406-412.

Research output: Contribution to journalArticle

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