This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The proposed research is designed to determine if increased dietary iron and iron stores contribute to the development of alcholic liver disease in African Americans. Our preliminary studies indicate that high dietary iron leads to increased hepatic iron stores in both Africans and African Americans, and that incrreased hepatic iron stores are associated with hepatic dysfunction in Africans who consume alcohol. We postulate that the oxidative environment induced by alcohol in heptocytes and Kupffer cell ( hepatic macrophages) leads to diassembly of the ironfur cluster of cytocolic aconitase/IRP 1 and conversion of this enzyme to an apoprotein that binds to RNA stem loops (iron repsonisve 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 transferrin 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 cell for NF-kB 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 contrributes to liver damage in the setting of alcoholic liver disease.
Specific Aim 1 : Determine if high dietary iron contributes to an alcohol-induced tendency for abnormally increased iron stores, 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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