Subcellular Zinc Deficiency Links with ER and Mitochondria Cell Death Signaling in Alcoholic Liver Disease, 2015 Mar 12, Am J Physiol Gastrointest Liver Physiol. Sun Q1, Zhong W2, Zhang W2, Li Q2, Sun X2, Tan X2, Sun X2, Dong D2, Zhou Z3.
- UNC greensboro.
- 2University of North Carolina at Greensboro.
- 3University of North Carolina at Greensboro email@example.com.
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 if 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 months. Chronic alcohol exposure significantly reduced hepatic and hepatocyte ER and mitochondria zinc levels. Among the detected zinc transporters, ER ZIP 13 and mitochondrial ZIP 8, which transport zinc from ER and mitochondria to cytosol, were significantly increased. However, mitochondrial ZnT4, which transport zinc from cytosol to mitochondria, was also increased. Hepatic p-eIF-2α, ATF4, and Chop were significantly upregulated, mitochondria 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 µM TPEN for 6 hours with or without supplementation with zinc or 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 µM but not by 2 mM NAC. These results suggest that chronic ethanol exposure induced ER and mitochondria zinc deficiency might activate intrinsic cell death signaling pathway, which could not be effectively rescued by antioxidant treatment.
Copyright © 2015, American Journal of Physiology- Gastrointestinal and Liver Physiology.