It has recently been estimated that 1 in 220 individuals in North America are homozygous for the hemochromatosis gene, thus identifying hereditary hemochromatosis as one of the most common inherited disorders. Complications of cirrhosis are the most common cause of death in these patients. Unfortunately, there is virtually nothing known about the mechanisms for the increased hepatic fibrogenesis and development of cirrhosis seen in chronic iron overload. Accordingly, the experiments described in this research application have been designed to answer specific questions about the mechanisms of fibrogenesis using an animal model of experimental hemochromatosis. Evidence for hepatic lipid peroxidation in chronic iron overload is well-established. Furthermore, it has recently been shown that aldehydic products of peroxidized lipids cause an increase in collagen gene expression and collagen synthesis in cultured human fibroblasts. For our experiments, hepatic iron overload will be produced using the carbonyl iron model of experimental hemochromatosis in the rat that has been developed and characterized in our laboratory over the past several years. In order to determine the role of lipid peroxidation in the hepatic fibrogenesis seen in dietary carbonyl iron overload, the carbonyl iron diet will be supplemented with the antioxidant alpha-tocopheryl acetate at levels sufficient to suppress hepatic lipid peroxidation. Various biochemical, molecular biological, and morphological techniques will be used to assess the effects of antioxidant supplementation on lipid peroxidation and fibrogenesis in chronic iron overload. The effects of aldehydic products of lipid peroxidation on lipocyte collagen gene expression and synthesis will be assessed using a variety of in vitro manipulations to lipocytes in culture. Finally, we will test the hypothesis that, in iron overload, Kupffer cell-derived products mediate an increase in collagen synthesis by lipocytes. The proposed experiments will directly test the hypothesis that iron-induced lipid peroxidation results in an increase in aldehydic byproducts, which can cause lipocytes to increase collagen gene expression and collagen synthesis resulting in fibrosis. Apart from the obvious clinical relevance to chronic iron overload conditions in humans, these investigations have broader significance to enhancing our understanding of the role of lipid peroxidation as an initiating event in conditions of increased hepatic fibrosis.
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