RGD Reference Report - Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways. - Rat Genome Database

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Zinc deficiency mediates alcohol-induced apoptotic cell death in the liver of rats through activating ER and mitochondrial cell death pathways.

Authors: Sun, Q  Zhong, W  Zhang, W  Li, Q  Sun, X  Tan, X  Sun, X  Dong, D  Zhou, Z 
Citation: Sun Q, etal., Am J Physiol Gastrointest Liver Physiol. 2015 May 1;308(9):G757-66. doi: 10.1152/ajpgi.00442.2014. Epub 2015 Mar 12.
RGD ID: 11553884
Pubmed: PMID:25767260   (View Abstract at PubMed)
PMCID: PMC4421018   (View Article at PubMed Central)
DOI: DOI:10.1152/ajpgi.00442.2014   (Journal Full-text)

Hepatic zinc deficiency has been well documented in alcoholic patients, but the mechanisms by which zinc deficiency mediates cell death have not been well defined. The objectives of this study were to determine whether alcohol perturbs subcellular zinc homeostasis and how organelle zinc depletion may link with cell death pathways. Wistar rats were pair-fed with the Lieber-DeCarli control or ethanol diet for 5 mo. Chronic alcohol exposure significantly reduced zinc level in isolated hepatic endoplasmic reticulum (ER) and mitochondria. Among the detected zinc transporters, ER Zrt/Irt-like protein (ZIP)13 and mitochondrial ZIP8, which transport zinc from ER and mitochondria to cytosol, were significantly increased. Mitochondrial zinc transporter (ZnT) 4, which transports zinc from cytosol to mitochondria, was also increased. ER phosphorylated eukaryotic initiation factor 2alpha, activating transcription factor 4, and C/EBP homologous protein were significantly upregulated, and mitochondrial cytochrome c release and Bax insertion were detected in association with caspase-3 activation and apoptotic cell death. To define the role of zinc deficiency in ER and mitochondrial stress, H4IIEC3 cells were treated with 3 muM N,N,N',N'-tetrakis (2-pyridylmethyl) ethylenediamine for 6 h with or without supplementation with zinc or N-acetylcysteine (NAC). The results demonstrated that zinc deprivation induced caspase-3 activation and apoptosis in association with ER and mitochondria dysfunction, which were inhibited by zinc as low as 10 muM but not by 2 mM NAC. These results suggest that chronic ethanol exposure induced in ER and mitochondrial zinc deficiency might activate intrinsic cell death signaling pathway, which could not be effectively rescued by antioxidant treatment.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Alcoholic Liver Diseases  ISOSlc39a13 (Rattus norvegicus)11553884; 11553884protein:increased expression:liver and endoplasmic reticulum (rat)RGD 
Alcoholic Liver Diseases  IEP 11553884protein:increased expression:liver and endoplasmic reticulum (rat)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Slc39a13  (solute carrier family 39 member 13)

Genes (Mus musculus)
Slc39a13  (solute carrier family 39 (metal ion transporter), member 13)

Genes (Homo sapiens)
SLC39A13  (solute carrier family 39 member 13)


Additional Information