Cirrhosis is the 11th leading cause of death in the United States. Alcohol remains a major cause of cirrhosis and no FDA approved therapy is available for alcoholic liver disease. There is increasing evidence that oxidative stress plays a pivotal role in the pathogenesis of alcoholic liver injury. Metallotbionein (MT) is a highly inducible, cysteine-rich, low-molecular weight protein that functions as a potent antioxidant. We propose to test the hypothesis that MT inhibits alcohol-induced oxidative stress, thereby preventing chronic alcohol-induced liver injury. The MT-overexpressing transgenic and MT-knockout mouse models will be used. These animals will be fed a liquid ethanol diet.
The specific aims and research approaches are as follows: (1) To determine whether MT confers resistance to chronic alcohol-related liver injury, the effect of MT on edmol-induced liver injury will be assessed by examining serum alanine aminotransferase and pathological changes in the liver. (2) To investigate possible mechanisms by which MT prevents chronic alcoholic liver injury, effects of MT on ethanol-induced oxidative stress and ethanol metabolism will be determined. (3) To evaluate whether suppression of mitochondrial oxidative injury plays a key role in the cytoprotection by MT, subcellular localization of MT, and ethanol-induced mitochondrial oxidative stress and subsequent fimetional changes will be examined. (4) To explore the possible clinical application of MT induction to prevent chronic alcohol-mediated liver injury, dietary zinc supplementation will be utilized to induce hepatic MT expression. Serum and hepatic zinc concentrations as well as hepatic MT concentrations will be measured. These studies will provide fundamental understanding of the role and possible clinical application of MT in cytoprotection against chronic alcohol-induced liver injury, a major clinical health problem without FDA approved therapy.
