TGF-beta and collagen-alpha 1 (I) gene expression are increased in hepatic acinar zone 1 of rats with iron overload.
We have shown that lipid peroxidation stimulates collagen-alpha 1 (I) gene transcription in cultured cells. Because iron is a transitional metal known to induce lipid peroxidation, we investigated whether hepatic lipid peroxidation modulates collagen gene expression in iron-overloaded rats. In this animal model of hemochromatosis, we show colocalization with iron in the hepatic acinar zone 1 of both lipid peroxidation and increased collagen-alpha 1 (I) transcripts, using immunohistochemistry for malondialdehyde-protein adducts and in situ hybridization, respectively. Iron overload stimulated the expression of the cytokine transforming growth factor-beta (TGF-beta) in acinar zone 1, in spite of the minor degree of hepatocellular necrosis and inflammation. The formation of reactive aldehydes and TGF-beta, both inducers of collagen gene expression, may play a role in the stimulation of hepatic collagen production in iron overload. These mechanisms could be a link between iron overload and fibrosis in genetic hemochromatosis.
Department of Medicine, Veterans Affairs Medical Center, San Diego, California.
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K
Houglum
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P
Bedossa
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M
Chojkier
D000818:Animals; D003094:Collagen / Q000145:classification / Q000235:genetics*; D015870:Gene Expression; D006432:Hemochromatosis / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D008054:Lipid Peroxides / Q000502:physiology; D008099:Liver / Q000503:physiopathology*; D008315:Malondialdehyde / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000235:genetics*
D008054:Lipid Peroxides; D011506:Proteins; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D008315:Malondialdehyde; D003094:Collagen; D007501:Iron