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Dietary Iron and Alcohol Liver Disease

Victor Gordeuk, M.D.
Principal Investigator, Howard University Hospital
vgordeuk@howard.edu

ABSTRACT

The proposed research is designed to determine if increased dietary iron and iron stores contribute to the development of alcoholic liver disease in African Americans.

Our preliminary studies indicate that high dietary iron leads to increased hepatic iron stores in both African and African Americans, and that increased hepatic iron stores are associated with hepatic dysfunction in Africans who consume alcohol.

We postulate that the oxidative environment induced by alcohol in hepatocytes and Kupffer cells (hepatic macrophages) leads to disassembly of the iron sulfur cluster of cytosolic aconitase/IRP1 and conversion of this enzyme to an apoprotein that binds to RNA stem loops (iron responsive elements-IREs) in iron metabolism transcripts. This non-physiologic increase in IRE-binding activity of IRP1 in turn leads to abnormal repression of ferritin synthesis and abnormal increases in transferring receptor synthesis and potentially toxic cytosolic labile iron concentrations. Based on our cell culture and animal model studies, we further postulate that increased non-heme iron content in Kupffer cells primes these cells for NF-κB activation and proinflammatory gene expression and thereby contributes to the pathogenesis of alcoholic liver disease in African Americans.

We aim to test two central hypotheses: (i) high dietary iron contributes to an alcohol-induced tendency for abnormal iron-loading of cells, and (ii) increased hepatic iron contributes to liver damage in the setting of alcoholic liver disease.

Specific Aim 1. Determine if high iron contributes to an alcohol-induced tendency for abnormally increased iron stores, liver dysfunction, and disordered mononuclear-macrophage iron metabolism in a cohort of predominantly African Americans who consume alcohol and in appropriate controls.

Specific Aim 2. Determine if alcohol-dependent oxidative stress leads to misregulated iron metabolism and if high iron stores potentiate resultant toxicity in clinically-indicated liver biopsy specimens from predominantly African-American patients with alcoholic liver disease and control patients undergoing liver biopsy for other reasons.

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