Hepatic zinc deficiency in alcoholic liver disease: dysregulation of zinc transporters and activation of mitochondrial apoptotic cell death pathway

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Qian Sun (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/
Zhanxiang Zhou

Abstract: Excessive alcohol consumption exerts health concerns, and alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the United States. However, there is still lack of an effective treatment. Zinc deficiency has been found in alcoholics over a half century ago. Experimental animals chronically exposed to alcohol exhibit decreased zinc level in the liver as well. Therefore, it is critical to determine the role of zinc deficiency in the pathogenesis of ALD. Our laboratory has repeatedly demonstrated that alcohol feeding significantly decreased hepatic zinc levels in rodents. In addition, clinical studies have shown that the severity of zinc deficiency is positively correlated with the stage of ALD. However, the mechanism that underlies alcohol-induced hepatic zinc deficiency is still unclear. Therefore, we hypothesized that dysregulation of hepatic zinc transporters, ZIP and ZnT, result in alcohol-induced zinc deficiency in the liver and decreased zinc levels in the liver enhanced intrinsic apoptotic cell death pathway via endoplasmic reticulum (ER) and mitochondrial stress. Aim 1 of this project investigated the expression of zinc transporters in alcohol- and pair-fed mice at different time points, along with the effect of reactive oxygen species (ROS) on the expression of zinc transporters. The results indicate that increased ROS due to chronic alcohol exposure altered the expression of zinc transporters, which account for the decrease in hepatic zinc level. Our laboratory also demonstrated that zinc deficiency contributes to ALD by decreasing ß-oxidation and blunting very low density lipoprotein (VLDL) secretion. Furthermore, zinc deficiency is associated with increased oxidative stress. Zinc supplementation protects against alcohol-induced liver injury. Given the fact that increased oxidative stress and impaired mitochondrial functions are closely linked with the pathogenesis of apoptosis and increased hepatic apoptosis plays a critical role in the development of ALD, the role of zinc deficiency in the pathogenesis of apoptosis was assessed in Aims 2 and 3. In Aim 2, increased endoplasmic reticulum (ER) stress indicated by C/EBP homologous protein (CHOP) expression after zinc deprivation was linked with the activation of mitochondrial apoptotic cell death pathway, which was partially dependent on oxidative stress. Data obtain in Aim 3 demonstrated that mitochondrial biogenesis regulators were downregulated by zinc deprivation, which resulted in defect of the mitochondrial electron transport chain. As a result, overproduction of ROS and decreased mitochondrial membrane potential occurred. Collectively, these findings provided critical insights into the molecular mechanisms of alcohol consumption-induced zinc deficiency and zinc deficiency-induced activation of apoptosis. However, we still need to investigate i) the direct effect of subcellular zinc deficiency on organelle functions, and ii) the beneficial effect of dietary zinc supplementation on subcellular zinc deficiency as well as organelle functions.

Additional Information

Language: English
Date: 2015
Alcoholic liver disease, Apoptosis, Endoplasmic reticulum, Mitochondria, Zinc, Zinc transporters
Alcoholic liver diseases
Alcohol $x Physiological effect
Alcoholism $x Complications
Liver $x Diseases
Zinc in the body
Zinc deficiency diseases
Endoplasmic reticulum

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