The Experts below are selected from a list of 1659 Experts worldwide ranked by ideXlab platform
Caroline A. Enns - One of the best experts on this subject based on the ideXlab platform.
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1 Hepatocyte-targeted HFE and TFR2 control hepcidin expression in mice
2016Co-Authors: Junwei Gao, Robert E. Fleming, Juxing Chen, Ivana De Domenico, David M. Koeller, Cary O. Harding, Dwight D. Koeberl, Caroline A. EnnsAbstract:Hereditary Hemochromatosis is caused by mutations in the hereditary Hemochromatosis Protein (HFE), transferrin-receptor 2 (TfR2), hemojuvelin, hepcidin or ferroportin genes. Hepcidin is a key iron-regulator, which is secreted by the liver and decreases serum-iron levels by causing the down-regulation of the iron-transporter, ferroportin. Mutations in either HFE or TfR2 lower hepcidin levels, implying that both HFE and TfR2 are necessary for the regulation of hepcidin-expression. In this study, we used a recombinant adeno-associated virus, AAV2/8, for hepatocyte-specific expression of either Hfe or Tfr2 in mice. Expression of Hfe in Hfe-null mice both increased Hfe- and hepcidin-mRNA and lowered hepatic iron and Tf-saturation. Expression of Tfr2 in Tfr2-deficient mice had a similar effect, whereas expression of Hfe in Tfr2-deficient mice or of Tfr2 in Hfe-null mice had no effect on liver or serum iron-levels. Expression of Hfe in wild-type mice increased hepcidin-mRNA and lowered iron-levels. In contrast, expression of Tfr2 had no effect on wild-type mice. These findings suggest that Hfe is limiting in the formation of th
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The Hereditary Hemochromatosis Protein, HFE, Inhibits Iron Uptake via Down-regulation of Zip14 in HepG2 Cells. J Biol Chem 2008;283:21462–21468. [PubMed: 18524764
2015Co-Authors: Junwei Gao, Juxing Chen, Maxwell Kramer, Hidekazu Tsukamoto, Caroline A. EnnsAbstract:The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary Hemochromatosis Protein, HFE. They have lower levels of hepcidin, than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the α3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE α3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf
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iron regulation by hepcidin
Journal of Clinical Investigation, 2013Co-Authors: Ningning Zhao, An Sheng Zhang, Caroline A. EnnsAbstract:Hepcidin is a key hormone that is involved in the control of iron homeostasis in the body. Physiologically, hepcidin is controlled by iron stores, inflammation, hypoxia, and erythropoiesis. The regulation of hepcidin expression by iron is a complex process that requires the coordination of multiple Proteins, including hemojuvelin, bone morphogenetic Protein 6 (BMP6), hereditary Hemochromatosis Protein, transferrin receptor 2, matriptase-2, neogenin, BMP receptors, and transferrin. Misregulation of hepcidin is found in many disease states, such as the anemia of chronic disease, iron refractory iron deficiency anemia, cancer, hereditary Hemochromatosis, and ineffective erythropoiesis, such as β-thalassemia. Thus, the regulation of hepcidin is the subject of interest for the amelioration of the detrimental effects of either iron deficiency or overload.
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Interaction of the hereditary Hemochromatosis Protein HFE with transferrin receptor 2 is required for transferrin-induced hepcidin expression.
Cell metabolism, 2009Co-Authors: Junwei Gao, Juxing Chen, Maxwell Kramer, Hidekazu Tsukamoto, An Sheng Zhang, Caroline A. EnnsAbstract:The mechanisms that allow the body to sense iron levels in order to maintain iron homeostasis are unknown. Patients with the most common form of hereditary iron overload have mutations in the hereditary Hemochromatosis Protein HFE. They have lower levels of hepcidin than unaffected individuals. Hepcidin, a hepatic peptide hormone, negatively regulates iron efflux from the intestines into the blood. We report two hepatic cell lines, WIF-B cells and HepG2 cells transfected with HFE, where hepcidin expression responded to iron-loaded transferrin. The response was abolished when endogenous transferrin receptor 2 (TfR2) was suppressed or in primary hepatocytes lacking either functional TfR2 or HFE. Furthermore, transferrin-treated HepG2 cells transfected with HFE chimeras containing only the alpha3 and cytoplasmic domains could upregulate hepcidin expression. Since the HFE alpha3 domain interacts with TfR2, these results supported our finding that TfR2/HFE complex is required for transcriptional regulation of hepcidin by holo-Tf.
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Heterotypic interactions between transferrin receptor and transferrin receptor 2
Blood, 2002Co-Authors: Todd M. Vogt, Aaron D. Blackwell, Anthony M. Giannetti, Pamela J. Bjorkman, Caroline A. EnnsAbstract:Cellular iron uptake in most tissues occurs via endocytosis of diferric transferrin (Tf) bound to the transferrin receptor (TfR). Recently, a second transferrin receptor, transferrin receptor 2 (TfR2), has been identified and shown to play a critical role in iron metabolism. TfR2 is capable of Tf-mediated iron uptake and mutations in this gene result in a rare form of hereditary Hemochromatosis unrelated to the hereditary Hemochromatosis Protein, HFE. Unlike TfR, TfR2 expression is not controlled by cellular iron concentrations and little information is currently available regarding the role of TfR2 in cellular iron homeostasis. To investigate the relationship between TfR and TfR2, we performed a series of in vivo and in vitro experiments using antibodies generated to each receptor. Western blots demonstrate that TfR2 Protein is expressed strongest in erythroid/myeloid cell lines. Metabolic labeling studies indicate that TfR2 Protein levels are approximately 20-fold lower than TfR in these cells. TfR and TfR2 have similar cellular localizations in K562 cells and coimmunoprecipitate to only a very limited extent. Western analysis of the receptors under nonreducing conditions reveals that they can form heterodimers.
Pierre Brissot - One of the best experts on this subject based on the ideXlab platform.
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liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in hfe Hemochromatosis
Hepatology, 2014Co-Authors: Edouard Bardoujacquet, Julie Philip, Richard Lorho, Martine Ropert, Marianne Latournerie, Pauline Housseldebry, Dominique Guyader, Olivier Loreal, Karim Boudjema, Pierre BrissotAbstract:Background: Defects in human Hemochromatosis Protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE- related hereditary Hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Methods: Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Results: Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (±99) µg/L. Magnetic resonance imaging showed that iron overload was absent in 9 patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis unmasked after liver transplantation. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; p<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at one and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. Conclusion: This study demonstrated that, in HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients that received LTs for other liver diseases. (HEPATOLOGY 2013.).
Edouard Bardoujacquet - One of the best experts on this subject based on the ideXlab platform.
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liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in hfe Hemochromatosis
Hepatology, 2014Co-Authors: Edouard Bardoujacquet, Julie Philip, Richard Lorho, Martine Ropert, Marianne Latournerie, Pauline Housseldebry, Dominique Guyader, Olivier Loreal, Karim Boudjema, Pierre BrissotAbstract:Background: Defects in human Hemochromatosis Protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE- related hereditary Hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Methods: Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Results: Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (±99) µg/L. Magnetic resonance imaging showed that iron overload was absent in 9 patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis unmasked after liver transplantation. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; p<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at one and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. Conclusion: This study demonstrated that, in HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients that received LTs for other liver diseases. (HEPATOLOGY 2013.).
Pamela J. Bjorkman - One of the best experts on this subject based on the ideXlab platform.
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Heterotypic interactions between transferrin receptor and transferrin receptor 2
Blood, 2002Co-Authors: Todd M. Vogt, Aaron D. Blackwell, Anthony M. Giannetti, Pamela J. Bjorkman, Caroline A. EnnsAbstract:Cellular iron uptake in most tissues occurs via endocytosis of diferric transferrin (Tf) bound to the transferrin receptor (TfR). Recently, a second transferrin receptor, transferrin receptor 2 (TfR2), has been identified and shown to play a critical role in iron metabolism. TfR2 is capable of Tf-mediated iron uptake and mutations in this gene result in a rare form of hereditary Hemochromatosis unrelated to the hereditary Hemochromatosis Protein, HFE. Unlike TfR, TfR2 expression is not controlled by cellular iron concentrations and little information is currently available regarding the role of TfR2 in cellular iron homeostasis. To investigate the relationship between TfR and TfR2, we performed a series of in vivo and in vitro experiments using antibodies generated to each receptor. Western blots demonstrate that TfR2 Protein is expressed strongest in erythroid/myeloid cell lines. Metabolic labeling studies indicate that TfR2 Protein levels are approximately 20-fold lower than TfR in these cells. TfR and TfR2 have similar cellular localizations in K562 cells and coimmunoprecipitate to only a very limited extent. Western analysis of the receptors under nonreducing conditions reveals that they can form heterodimers.
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the Hemochromatosis Protein hfe competes with transferrin for binding to the transferrin receptor
Journal of Molecular Biology, 1999Co-Authors: Jose Lebron, Anthony P West, Pamela J. BjorkmanAbstract:HFE is a class I major histocompatibility complex (MHC)-related Protein that is mutated in patients with the iron overload disease hereditary Hemochromatosis. HFE binds to transferrin receptor (TfR), the receptor used by cells to obtain iron in the form of diferric transferrin (Fe-Tf). Previous studies demonstrated that HFE and Fe-Tf can bind simultaneously to TfR to form a ternary complex, and that membrane-bound or soluble HFE binding to cell surface TfR results in a reduction in the affinity of TfR for Fe-Tf. We studied the inhibition by soluble HFE of the interaction between soluble TfR and Fe-Tf using radioactivity-based and biosensor-based assays. The results demonstrate that HFE inhibits the TfR:Fe-Tf interaction by binding at or near the Fe-Tf binding site on TfR, and that the Fe-Tf:TfR:HFE ternary complex consists of one Fe-Tf and one HFE bound to a TfR homodimer.
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crystal structure of the Hemochromatosis Protein hfe and characterization of its interaction with transferrin receptor
Cell, 1998Co-Authors: Jose Lebron, John N Feder, Melanie J Bennett, Daniel E Vaughn, Arthur J Chirino, Peter M Snow, Gabriel Mintier, Pamela J. BjorkmanAbstract:HFE is an MHC-related Protein that is mutated in the iron-overload disease hereditary Hemochromatosis. HFE binds to transferrin receptor (TfR) and reduces its affinity for iron-loaded transferrin, implicating HFE in iron metabolism. The 2.6 A crystal structure of HFE reveals the locations of Hemochromatosis mutations and a patch of histidines that could be involved in pH-dependent interactions. We also demonstrate that soluble TfR and HFE bind tightly at the basic pH of the cell surface, but not at the acidic pH of intracellular vesicles. TfR:HFE stoichiometry (2:1) differs from TfR:transferrin stoichiometry (2:2), implying a different mode of binding for HFE and transferrin to TfR, consistent with our demonstration that HFE, transferrin, and TfR form a ternary complex.
Julie Philip - One of the best experts on this subject based on the ideXlab platform.
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liver transplantation normalizes serum hepcidin level and cures iron metabolism alterations in hfe Hemochromatosis
Hepatology, 2014Co-Authors: Edouard Bardoujacquet, Julie Philip, Richard Lorho, Martine Ropert, Marianne Latournerie, Pauline Housseldebry, Dominique Guyader, Olivier Loreal, Karim Boudjema, Pierre BrissotAbstract:Background: Defects in human Hemochromatosis Protein (HFE) cause iron overload due to reduced hepatic hepcidin secretion. Liver transplantation (LT) is a key treatment for potential complications from HFE- related hereditary Hemochromatosis (HH). This study evaluated hepcidin secretion and iron burden after LT to elucidate HH pathophysiology. Methods: Patients (n=18) homozygous for the p.Cys282Tyr mutation in the HFE gene underwent LT between 1999 and 2008. Serum iron, serum hepcidin, and hepatic iron concentrations were determined before LT and at the end of follow-up (median 57 months). Mortality and causes of death were determined. Survival was compared to that of the overall patient population that received LT. Results: Before LT, serum hepcidin levels were low (0.54 ± 2.5 nmol/L; normal range: 4-30 nmol/L). After LT, 11 patients had iron evaluations; none received iron depletion therapy; all had normal transferrin saturation. The mean serum ferritin was 185 (±99) µg/L. Magnetic resonance imaging showed that iron overload was absent in 9 patients, mild in one patient with metabolic syndrome, and high (180 µmol/g) in one patient with hereditary spherocytosis unmasked after liver transplantation. At the end of follow-up, serum hepcidin was normal in 10 patients (11.12 ± 7.6 nmol/L; p<0.05) and low in one patient with iron deficiency anemia. Survival was 83% and 67% at one and 5 years, respectively. Survival was similar for patients with HH and patients that received LT for other causes. Conclusion: This study demonstrated that, in HH, LT normalized hepcidin secretion and prevented recurrence of hepatic iron overload. Survival was similar to that of patients that received LTs for other liver diseases. (HEPATOLOGY 2013.).