Pancreatic β-cells express hepcidin, an iron-uptake regulatory peptide

Kulaksiz, Hasan; Fein, Evelyn; Redecker, P.; Stremmel, Wolfgang; Adler, Guido; Cetin, Yalcin

doi:10.1677/joe-07-0528

Cited by 109 publications

(100 citation statements)

References 38 publications

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“…Hepcidin is also expressed at lower levels in other organs such as the heart, brain, spinal cord, stomach, and pancreas and in cells such as adipocytes and macrophages (Merle et al 2007, Kulaksiz et al 2008, Hanninen et al 2009, Isoda et al 2010. Increases in the concentration of iron and inflammation upregulate the transcription of hepcidin, while iron deficiency and hypoxia downregulate it (Nicolas et al 2002).…”

Section: Introductionmentioning

confidence: 99%

Friend of GATA suppresses the GATA-induced transcription of hepcidin in hepatocytes through a GATA-regulatory element in the HAMP promoter

Bagu

Santos²

2011

Journal of Molecular Endocrinology

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Hepcidin is an antimicrobial peptide hormone involved in the metabolism of iron, encoded for by the HAMP gene mainly in hepatocytes. It's expressed at lower levels in other cells such as the macrophages. The mechanisms that determine tissue-specific expression of hepcidin remain unclear. GATA-and its co-factor Friend of GATA (FOG) modulate the tissue-specific transcription of other genes involved in the metabolism of iron. GATA proteins are group of evolutionary conserved transcriptional regulators that bind to the consensus motif -WGATAR-in the promoter. We characterized a 1 . 3 kb fragment of the 5 0 -flanking sequence of the HAMP gene in Huh7 cells, which express HAMP. Transfection of 5 0 -deletions of the HAMP promoter in Huh7 cells revealed two regions, K932/K878 and K155/K96, that when deleted decreased promoter activity. Using site-directed mutations in the HAMP promoter region K155/K96 we identified two subregions, K138/K125 and K103/K98, which when mutated suppressed promoter activity by 70 and 90% respectively. Site K103/K98 with a sequence -TTATCT-to which endogenous GATA proteins 4 and 6 bind and transactivate HAMP is a GATA-regulatory element (RE). Mutation of the GATA-RE abrogated binding of GATA proteins 4 and 6 to the promoter and blunted the GATA transactivation of HAMP. FOG proteins 1 and 2 suppressed the endogenous and exogenous GATA activation of the HAMP promoter. We concluded that the GATA-RE, -TTATCT-in the HAMP promoter region K103/K98 is crucial for the GATA-4 and GATA-6 driven transcription of hepcidin in Huh7 cells and that FOG proteins moderate the transcription by suppressing the GATA transactivation of HAMP.

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Section: Introductionmentioning

confidence: 99%

Friend of GATA suppresses the GATA-induced transcription of hepcidin in hepatocytes through a GATA-regulatory element in the HAMP promoter

Bagu

Santos²

2011

Journal of Molecular Endocrinology

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“…Hepcidin immunoreactive cells in the guinea pig pancreas were found exclusively in Langerhans islets. In human and rat pancreas, the hepcidin-positive cells were clearly identified as insulin-producing b-cells by their typical localization within the Langerhans islets and by co-localization of hepcidin and insulin (Kulaksiz et al 2008), assuming that in the guinea pig the endogenous hepcidin-positive cells are b-cells, too. In the guinea pig kidney, hepcidin was localized to epithelial cells of renal tubules, while no hepcidin immunoreactivity was observed in the glomerulus.…”

Section: Discussionmentioning

confidence: 99%

Identification, sequencing, and cellular localization of hepcidin in guinea pig (Cavia porcellus)

Schwarz

Strnad²,

Singer³

et al. 2009

Journal of Endocrinology

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Hepcidin, a cysteine-rich peptide hormone with antimicrobial and iron-regulatory activity, plays a central role in regulating iron metabolism during inflammation, hypoxia, iron deficiency, and iron overload. The aim of this study was to isolate and sequence the guinea pig hepcidin gene and show peptide's tissue distribution to identify the guinea pig as good animal model to study the regulation and function of hepcidin. The guinea pig hepcidin cDNA contains a 252 bp open reading frame encoding for an 83 amino acid protein with eight highly conserved cysteine residues. Phylogenetic analyses showed that guinea pig hepcidin was more related to human and chimpanzee than to rodents like mouse or rat. RT-PCR studies revealed that hepcidin mRNA was most abundant in liver, less ample in pancreas, heart, and kidney and not detectable in lung and biliary system. Western blot analyses showed a distinct immunoreactive band of w8 kDa, consistent with the predicted size of prohepcidin, and revealed that guinea pig hepcidin protein is synthesized predominantly in the liver, and with lower expression in kidney, heart, and pancreas. Immunohistochemical studies showed hepcidin predominantly at the basolateral membrane domain of hepatocytes in periportal regions. In pancreas, hepcidin immunoreactivity was confined to endocrine islets of Langerhans, while hepcidin was seen in tubules, but not in the glomeruli in the kidney. Our data identify guinea pig as a convenient model organism to study the role of hepcidin, given the remarkable sequence similarity and tissue distribution pattern largely identical to human.

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“…Although hepcidin is produced mainly by the hepatocytes, many other cells/tissues are able to synthesize the hormone [12][13][14][15][16][17]. However, the exact physiological role of the extra-hepatocytic hepcidin is still unknown.…”

Section: Introductionmentioning

confidence: 99%

Heme Activates Macrophage Hepcidin Expression via Toll like Receptor 4 and Extracellular Signal-Regulated Kinases Signaling Pathway

Nk¹,

M²

2017

Clin Pharmacol Biopharm

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Tight regulation of systemic and cellular iron levels is required for good health. This control is ensured by hepcidin, a small peptide hormone produced predominantly by the liver. Lack of hepcidin expression or mutations affecting regulators of hepcidin expression, cause common genetic iron disorders. Hepcidin is also expressed in myeloid cells and its expression is increased after infections and in response to lipopolysaccharide. Our study uncovers that macrophages rapidly increase hepcidin expression in response to excess of heme. Moreover, we demonstrate that the underlying mechanism by which heme triggers hepcidin activation in macrophages depends on the Toll Like Receptor (TLR)-4 and the contribution of Extracellular Signal-Regulated Kinases (ERK) pathway. Our data propose the contribution of hepcidin, locally produced by macrophages, to the pathology of disorders characterized by excess of free heme, such as certain bacterial infections and hemolytic disorders. Finally, using macrophages from Hfe-deficient mice, we demonstrate that the lack of Hfe is not critical for the hepcidin induction by heme but is required to maintain basal hepcidin expression in macrophages. The findings that the levels of hepcidin in macrophages are directly controlled by the actions of Hfe in these cells expand our view on Hfe beyond the liver and as mere regulator of iron levels.

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Pancreatic β-cells express hepcidin, an iron-uptake regulatory peptide

Cited by 109 publications

References 38 publications

Friend of GATA suppresses the GATA-induced transcription of hepcidin in hepatocytes through a GATA-regulatory element in the HAMP promoter

Friend of GATA suppresses the GATA-induced transcription of hepcidin in hepatocytes through a GATA-regulatory element in the HAMP promoter

Identification, sequencing, and cellular localization of hepcidin in guinea pig (Cavia porcellus)

Heme Activates Macrophage Hepcidin Expression via Toll like Receptor 4 and Extracellular Signal-Regulated Kinases Signaling Pathway

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