A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

Gutschow, Patrick; Schmidt, Paul; Han, Huiling; Ostland, V. E.; Bartnikas, Thomas B.; Pettiglio, Michael A.; Herrera, Carolina; Butler, James S.; Nemeth, Elizabeta; Ganz, Tomas; Fleming, Mark D.; Westerman, Mark

doi:10.3324/haematol.2014.116723

Cited by 29 publications

(20 citation statements)

References 46 publications

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“…The circulating hepcidin concentration is fundamentally regulated at the gene (Hamp) transcription level in hepatocytes. 7,8,10 Each ESA significantly suppressed Hamp mRNA expression in ISAM livers 48 hours after administration ( Figure 1C). At 6 hours after administration, C.E.R.A.…”

Section: © Ferrata Storti Foundationmentioning

confidence: 91%

“…Consistently, the unsaturated iron binding capacity of transferrin (UIBC) in the peripheral blood was decreased, and the serum level of hepcidin, a peptide hormone that inhibits iron entry into circulation, 7,8 was increased in ISAM. In addition, we found that EPO deficiency seems to be indirectly related to both systemic hypoxia and cardiomegaly through chronic severe anemia in mature ISAM (Online Supplementary Figure S1B and C).…”

Section: A B Cmentioning

confidence: 93%

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Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Suzuki

Sasaki²,

Kato

et al. 2016

Haematologica

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Section: © Ferrata Storti Foundationmentioning

confidence: 91%

Section: A B Cmentioning

confidence: 93%

Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Suzuki

Sasaki²,

Kato

et al. 2016

Haematologica

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“…In addition, hepcidin mRNA expression is again unchanged in thalassemic relative to WT mice and increased in apoTf-treated thalassemic mice. 13 A mouse serum hepcidin ELISA has recently been developed 37 and demonstrates a strong correlation with hepcidin mRNA. Increased hepcidin expression in apoTf-treated thalassemic mice occurs despite decreased serum or liver iron, cytosolic Ferritin H, and circulating transferrin saturation, as previously reported, 13 and thus does not reflect changes in iron status.…”

Section: Discussionmentioning

confidence: 99%

Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation

Chen

Choesang

et al. 2015

Haematologica

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Iron overload results in significant morbidity and mortality in β-thalassemic patients. Insufficient hepcidin is implicated in parenchymal iron overload in β-thalassemia and approaches to increase hepcidin have therapeutic potential. We have previously shown that exogenous apo-transferrin markedly ameliorates ineffective erythropoiesis and increases hepcidin expression in Hbb th1/th1 (thalassemic) mice. We utilize in vivo and in vitro systems to investigate effects of exogenous apo-transferrin on Smad and ERK1/2 signaling, pathways that participate in hepcidin regulation. Our results demonstrate that apo-transferrin increases hepcidin expression in vivo despite decreased circulating and parenchymal iron concentrations and unchanged liver Bmp6 mRNA expression in thalassemic mice. Hepatocytes from apo-transferrin-treated mice demonstrate decreased ERK1/2 pathway and increased serum BMP2 concentration and hepatocyte BMP2 expression. Furthermore, hepatocyte ERK1/2 phosphorylation is enhanced by neutralizing anti-BMP2/4 antibodies and suppressed in vitro in a dose-dependent manner by BMP2, resulting in converse effects on hepcidin expression, and hepatocytes treated with MEK/ERK1/2 inhibitor U0126 in combination with BMP2 exhibit an additive increase in hepcidin expression. Lastly, bone marrow erythroferrone expression is normalized in apo-transferrin treated thalassemic mice but increased in apo-transferrin injected wild-type mice. These findings suggest that increased hepcidin expression after exogenous apo-transferrin is in part independent of erythroferrone and support a model in which apo-transferrin treatment in thalassemic mice increases BMP2 expression in the liver and other organs, decreases hepatocellular ERK1/2 activation, and increases nuclear Smad to increase hepcidin expression in hepatocytes.

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“…Serum glucose, ferritin, and liver enzymes aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were determined using the Beckman DXC 800 Analyzer (Brea, CA). Serum hepcidin levels were measured in the serum using the Murine Hepcidin Compete™ ELISA developed by Intrinsic Lifesciences (La Jolla, CA) (10). Hepatic malonyldialdehyde (MDA) levels and hepatic triglyceride levels were quantified using the TBARS Assay Kit (Cayman, Ann Arbor, MI) and the Triglyceride Quantification Kit (MBL International, Woburn, MA), respectively, following the manufacturers' instructions.…”

Section: Animals and Diet Five-week-old Male B6bks(d)-leprmentioning

confidence: 99%

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

Handa

Morgan-Stevenson

Maliken³

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

116

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MM, Kowdley KV. Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice. Am J Physiol Gastrointest Liver Physiol 310: G117-G127, 2016. First published November 12, 2015; doi:10.1152/ajpgi.00246.2015.-The aim of this study was to determine the effect of iron overload in the development of nonalcoholic steatohepatitis (NASH) in a genetically obese mouse model (Lepr db/db ). Leptin receptor-deficient mice were fed a normal or an iron-supplemented chow for 8 wk and switched to normal chow for 8 wk. All dietary iron (DI)-fed mice developed hepatic iron overload predominantly in the reticuloendothelial system. Hepatocellular ballooning injury was observed in the livers of 85% of DI mice, relative to 20% of chow-fed Lepr db/db . Hepatic malonyldialdehyde levels and mRNA levels of antioxidant genes (Nrf2, Gpx1, and Hmox1) were significantly increased in the DI mice. Hepatic mRNA levels of mitochondrial biogenesis regulators Pgc1␣, Tfam, Cox4, and Nrf1 were diminished in the DI mice. In addition, gene expression levels of cytokines (Il6, Tnf␣) and several innate and adaptive immune cell markers such as Tlr4, Inos, CD11c, CD4, CD8, and Ifn␥ were significantly increased in livers of the DI group. Strikingly, Nlrp3, a component of the inflammasome and Il18, a cytokine elicited by inflammasome activation, were significantly upregulated in the livers of DI mice. In addition, RAW 264.7 macrophages loaded with exogenous iron showed significantly higher levels of inflammatory markers (Inos, Tnf␣, Mcp1, Tlr4). Thus dietary iron excess leads to hepatic oxidative stress, inflammasome activation, induction of inflammatory and immune mediators, hepatocellular ballooning injury, and therefore NASH in this model. Taken together, these studies indicate a multifactorial role for iron overload in the pathogenesis of NASH in the setting of obesity and metabolic syndrome. iron excess; hepatocellular ballooning; inflammasome; immune cell activation; reticuloendothelial system NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) is the most prevalent chronic liver disease in the world and is strongly associated with obesity and the attendant metabolic syndrome (17

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A competitive enzyme-linked immunosorbent assay specific for murine hepcidin-1: correlation with hepatic mRNA expression in established and novel models of dysregulated iron homeostasis

Cited by 29 publications

References 46 publications

Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Efficacy estimation of erythropoiesis-stimulating agents using erythropoietin-deficient anemic mice

Increased hepcidin in transferrin-treated thalassemic mice correlates with increased liver BMP2 expression and decreased hepatocyte ERK activation

Iron overload results in hepatic oxidative stress, immune cell activation, and hepatocellular ballooning injury, leading to nonalcoholic steatohepatitis in genetically obese mice

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