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1 Departments of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA, USA; Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA; The Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA
2 Departments of Medicine, Louisiana State University Health Sciences Center, Shreveport, LA, USA; The Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, USA
* To whom correspondence should be addressed. E-mail: kyeh{at}lsuhsc.edu.
Hepcidin has been implicated as the iron stores regulator: a hepatic signaling molecule that regulates intestinal iron absorption by undefined mechanisms. The possibility that hepcidin regulates the expression of ferroportin 1 (FPT1), the basolateral iron transporter was examined in rats after administration of lipopolysaccharide (LPS), an iron chelator, or His-tagged recombinant hepcidin (His-rHepc). In the liver, LPS stimulated a biphasic increase of hepcidin mRNA with peaks of mRNA at 6 h and 36 h. Concurrent ly hepatic FPT1 mRNA expression decreased to minimal level at 6 h and then increased with a peak at 24-36 h. LPS also induced biphasic changes in intestinal FPT1 mRNA expression with decreased levels at 6 h and increased expression at 48 h. While the initial decrease of FPT1 coincides with a LPS-induced decrease in serum iron, both intestinal and hepatic FPT1 expression recovered while serum iron concentration continued to decrease for at least 24 hours. Dietary iron ingestion increased intestinal ferritin protein production, but did not reduce intestinal FPT1 mRNA expression. The iron chelator pyrrolidinedithiocarbamate (PDTC) stimulated hepatic hepcidin without suppressing intestinal FPT1 expression. In PDTC-treated rats, LPS stimulated no additional hepatic hepcidin expression, but did increase intestinal FPT1 expression. Administration of His-rHepc induced significant reduction of intestinal FPT1 expression. Taken together, the data suggest that hepcidin mediates LPS-induced down regulation of intestinal FPT1 expression and that the hepcidin signaling pathway involves a PDTC-sensitive step.
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