Autophagy is a cellular catabolic process by which damaged organelles, protein aggregates and lipid droplets become degraded in lysosomes. Autophagy plays an important role in the mitigation of ethanol induced liver damage by removing lipid droplets and damaged mitochondria. The role of zinc in autophagy has just begun to be investigated. Accumulating evidence indicates that zinc is critical for autophagy. Hence, the protective roles of autophagy may be compromised when dietary zinc is low. Conversely, high zinc intake may confer protection against ethanol induced liver injury by promoting autophagy. It is known that zinc supplementation protects against ethanol toxicity. However, the potential role of autophagy as a mediator of zinc protective effects has not been investigated. This project seeks to investigate the role of zinc in autophagy during ethanol exposure.
Two specific aims that complement each other are proposed.
Aim 1 involves the characterization of the impact of zinc deficiency, adequacy and excess on autophagy in liver in mice acutely exposed to ethanol.
In aim 2, autophagy will be examined in human hepatoma cells treated with various levels of zinc and ethanol. Autophagic flux, liver damage and lipid accumulation will be evaluated in presence an absence of autophagy inhibitors. In addition, in aim 2, fluorescent probes will be utilized to label autophagosomes, mitochondria, lipid droplets and labile zinc. This will allow a more complete characterization of the role of zinc in autophagy. The results of the proposed work will advance our understanding of how zinc intake influences the development of alcohol induced diseases such as alcoholic liver disease and will provide guidance for future research.
Alcohol induced diseases such as alcohol liver disease are a major cause of illness and death in the United States. Recent studies have indicated that autophagy is an adaptive process that protects against ethanol toxicity. Understanding how autophagy is influenced by zinc intake will help underscore the importance of having an adequate zinc intake in the prevention and treatment of alcohol induced diseases.
|Liuzzi, Juan P; Guo, Liang; Yoo, Changwon et al. (2014) Zinc and autophagy. Biometals 27:1087-96|