Alcoholism and alcoholic liver disease are often associated with disturbances to iron homeostasis, ranging from iron deficiency anemia to hemochromatosis and siderosis. Since the liver is not only a major site of iron storage, but also synthesizes transferrin, the major plasma iron transport protein, any hepatic dysfunction, such as that caused by alcohol may result in dramatic alterations to iron metabolism in this organ. It is therefore the primary aim of this project to assess the influence of alcohol on liver iron homeostasis in the rat, as well as other factors such as circulating endotoxins (which are increased in alcoholic liver disease). Since fatty acids have been implicated in iron transport and fatty acid metabolism is disturbed by alcohol, it is also a secondary aim to examine their role in the altered iron metabolism associated with alcohol To achieve these aims, the following goals will be met: (1) The effects of iron loading or depletion will be examined in hepatocytes and Kupffer cells from alcoholic rate in vivo and in vitro. Transferrin iron uptake, ferritin synthesis, cellular iron mobilization and transferrin receptor concentration and rate of recycling will be quantitated. (2) The cellular control of transferrin receptors in these animals will be investigated. The rate of messenger and protein synthesis will be measured, as will degradation. This system will be compared to that for asialoglycoproteins and the synthesis and secretion of transferrin and ferritin. (3) The effects of endotoxins on iron metabolism in alcoholic rats will be analyzed further, using the systems above. The long-term effects of the induction of antibody titers to endotoxins in these rate will also be examined. (4) The relationship of fatty acid uptake to iron metabolism will be assessed in acute and chronic alcoholic rats. Both gut and liver uptake will be analyzed, using duodenal loops, isolated cells and membrane vesicles. It is anticipated that extrapolation to the human disease state will be greatly facilitated by these studies and will lead to a better understanding of the disturbances of iron metabolism that occur in alcoholics and alcoholic liver disease.
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