title: Iron overload in mice expressing HFE exclusively in the intestinal villi provides evidence that HFE regulates a functional cross-talk between crypt and villi enterocytes.
abstract: Hereditary hemochromatosis (HH), a common autosomal recessive disorder due to a mutation in HFE, which encodes an atypical MHC class I glycoprotein, is characterized by excessive absorption of dietary iron. Little is known however of the apparently complex pathophysiology of HFE involvement in the process of iron influx. Here, in order to tackle the issue in vivo, we decided to target HFE expression exclusively to the relevant tissue, intestinal epithelium. This was achieved by putting HFE under transcriptional control of the rat fatty acid binding protein (Fabpi) promoter. Quite unexpectedly, Fabpi-HFE mice had significantly elevated serum transferrin saturation levels in comparison to those of normal littermates. By a careful, layer by layer analysis of transgene expression along the crypt-villus axis, we were able to affirm that the ectopic expression of transgenic HFE in the differentiated villi enterocytes was responsible for ferric hyperabsorption, a phenomenon exacerbated in the absence of endogenous HFE expression, which we assessed by crossing the transgene onto an HFE(-/-) (knockout) background. This forced dichotomy between the absence of HFE in the crypt and expression in the villi provides experimental support that HFE functions as a "gatekeeper," regulating the cross-talk between the crypt and villi enterocytes and thereby modulating the avidity of mature enterocytes for dietary iron.
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D002450:Cell Communication; D020895:Enterocytes / Q000378:metabolism*; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D005260:Female; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007413:Intestinal Mucosa / Q000033:anatomy & histology / Q000166:cytology / Q000378:metabolism*; D007501:Iron / Q000032:analysis / Q000378:metabolism; D019190:Iron Overload / Q000209:etiology* / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics; D051381:Rats; D014018:Tissue Distribution; D014168:Transferrin / Q000378:metabolism; D019076:Transgenes
chemical_list: D002352:Carrier Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; C490174:Fabp7 protein, rat; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; C484232:HFE protein, rat; D000071020:Hemochromatosis Protein; C499535:Hfe protein, mouse; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D014168:Transferrin; D007501:Iron