scholarly journals Serotonin regulates hepcidin expression via a gut-liver axis

2021 ◽  
Author(s):  
Tereza Coman ◽  
Marion Falabregue ◽  
Julien Rossignol ◽  
Pierre Bonneau ◽  
Morgane Djebar ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Iron Regulation ◽  
Serotonin Level ◽  
Prognostic Impact ◽  
Physiological Factor ◽  
Hepcidin Expression ◽  
Brain Neurotransmitter ◽  
Dependent Pathway ◽  
5Ht2b Receptor ◽  
Pathological Situation

Liver hepcidin, is well recognized as the central hormone of systemic iron regulation. Although serotonin is most recognized as a brain neurotransmitter, prodigious quantities are synthesized in gut enterochromaffin cells and several lines of evidence, also identified the gut as an essential sensor and regulator of iron homeostasis. Using a mouse model deficient for peripheral serotonin (Tph1 KO), we identified gut-derived serotonin as a key physiological factor in hepcidin regulation. Serotonin represses hepcidin's through a 5HT2B receptor-dependent pathway, independently of any other known hepcidin regulators, including bone marrow signals. This regulation is conserved in humans and shows physiological significance as a negative correlation between serotonin and hepcidin levels was observed in a cohort of healthy individuals. Moreover, in pathological situation such as acute heart failure, where iron deficiency has a negative prognostic impact, we provide evidence that an increase in serotonin level seems necessary to repress hepcidin level, to increase iron availability.

scholarly journals Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4

Blood ◽  
2007 ◽  
Vol 110 (6) ◽  
pp. 2182-2189 ◽  
Author(s):  
Lan Lin ◽  
Erika V. Valore ◽  
Elizabeta Nemeth ◽  
Julia B. Goodnough ◽  
Victoria Gabayan ◽  
...  
Keyword(s):  
Cell Lines ◽  
Culture System ◽  
Iron Homeostasis ◽  
Transferrin Saturation ◽  
Peptide Hormone ◽  
Iron Regulation ◽  
Primary Hepatocytes ◽  
Primary Hepatocyte Culture ◽  
Hepcidin Mrna ◽  
Dependent Pathway

Abstract The peptide hormone hepcidin is the principal regulator of systemic iron homeostasis. We examined the pathway by which iron stimulates the production of hepcidin. In humans who ingested 65 mg of iron, the increase in transferrin saturation preceded by hours the increase in urinary hepcidin excretion. Increases in urinary hepcidin concentrations were proportional to the increment in transferrin saturation. Paradoxically, in previous studies in primary hepatocytes and cell lines, hepcidin response to iron or iron transferrin was not observed. We now report that freshly isolated murine primary hepatocytes responded to holotransferrin but not apotransferrin by increasing hepcidin mRNA. Hepcidin increase was not due to contamination of the transferrin preparations by endotoxin, a potent pathologic stimulus of hepcidin synthesis. Using this culture system, we showed that holotransferrin concentrations regulate hepcidin mRNA concentrations through a hemojuvelin/BMP2/4–dependent pathway. Although BMP9 is known to be expressed in the liver and potently increased the basal concentrations of hepcidin mRNA, it did not interact with hemojuvelin, and interference with its signaling pathway did not affect iron regulation. Fresh primary hepatocytes constitute a sufficient system for the regulation of hepcidin by physiologic iron stimuli and will greatly facilitate studies of major disorders of iron homeostasis.

Age and gender dependent differences in BMP6 mediated hepcidin expression and iron homeostasis

2011 ◽  
Vol 49 (01) ◽  
Author(s):  
S Arndt ◽  
U Mägdefrau ◽  
C Dorn ◽  
K Schardt ◽  
C Hellerbrand ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Age And Gender ◽  
Hepcidin Expression ◽  
And Gender

Abstract 293: Mammalian Target of Rapamycin and Tristetraprolin Regulate Iron Homeostasis in Cardiac Cells

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Marina Bayeva ◽  
Arineh Khechaduri ◽  
Hossein Ardehali
Keyword(s):  
Energy Metabolism ◽  
Iron Homeostasis ◽  
Heart Function ◽  
Iron Regulation ◽  
Mrna Levels ◽  
Iron Regulatory Proteins ◽  
Regulatory Pathways ◽  
Genetic Knockout ◽  
Cellular Iron ◽  
Vital Functions

Introduction: Iron is essential for normal heart function, and disruption of iron homeostasis can lead to cardiomyopathy. However, our understanding of iron regulation on a cellular level is incomplete, with a single model involving iron regulatory proteins (IRP) described to date. Here, we report the existence of a parallel iron regulatory pathway by energy sensor mTOR and inflammatory mediator trsitetraprolin (TTP). Results: To examine the role of energy metabolism in the regulation of cellular iron, we used rapamycin to inhibit mTOR pathway in H9c2 cardiac myoblasts and mouse embryonic fibroblasts (MEFs). Rapamycin treatment significantly elevated cellular iron content through a coordinated reduction in iron import (transferrin receptor, TfR1) and iron export (ferroportin, Fpn1), leading to deceleration of iron flux and net iron accumulation. We found that the primary action of rapamycin was to reduce TfR1 through destabilization of its mRNA. Surprisingly, this effect was not mediated by IRP1/2, the “classical” sensors of cellular iron levels, as TfR1 mRNA levels were significantly reduced by rapamycin even in cells with the genetic knockout of IRP1 and IRP2. In yeast, a tandem zinc finger (TZF) protein Cth2 was found to conserve cellular iron in states of deficiency by preferentially degrading mRNA of non-essential iron-containing proteins thus reducing iron requirements and liberating iron for vital functions. We found that the mammalian TZF protein TTP, an established mediator of inflammation, was greatly induced by iron deficiency, enhanced degradation of iron-containing proteins, and complemented Cth2 deletion in yeast, thus establishing TTP as the functional homolog of Cth2 in mammalian iron regulation. Finally, TTP levels were increased by rapamycin in IRP1/2-independent manner, and genetic knockout of TTP in MEFs significantly reversed the effects of rapamycin on TfR1 mRNA levels and stability. These findings establish TTP as the mediator of iron-regulatory effects of mTOR and provide a novel link between energy metabolism, inflammation and iron regulatory pathways. Conclusions: We identified a novel pathway of cellular iron regulation by mTOR and TTP, which complements the “classical” IRP1/2 model.

Kupffer cells modulate iron homeostasis in mice via regulation of hepcidin expression

2008 ◽  
Vol 86 (7) ◽  
pp. 825-835 ◽  
Author(s):  
Milan Theurl ◽  
Igor Theurl ◽  
Kathrin Hochegger ◽  
Peter Obrist ◽  
Nathan Subramaniam ◽  
...  
Keyword(s):  
Kupffer Cells ◽  
Iron Homeostasis ◽  
Hepcidin Expression

Hepcidin inhibition improves iron homeostasis in ferrous sulfate and LPS treatment model in mice

Drug Research ◽  
2021 ◽  
Author(s):  
Vishal Patel ◽  
Amit Joharapurkar ◽  
Samadhan Kshirsagar ◽  
Maulik Patel ◽  
Hiren Patel ◽  
...  
Keyword(s):  
Ferrous Sulfate ◽  
Serum Iron ◽  
Iron Homeostasis ◽  
The Body ◽  
Rapid Screening ◽  
Iron Dextran ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Serum Hepcidin ◽  
Lps Treatment

Abstract Background Hepcidin, a liver-derived peptide, regulates the absorption, distribution, and circulation of iron in the body. Inflammation or iron overload stimulates hepcidin release, which causes the accumulation of iron in tissues. The inadequate levels of iron in circulation impair erythropoiesis. Inhibition of hepcidin may increase iron in circulation and improve efficient erythropoiesis. Activin-like kinase (ALK) inhibitors decrease hepcidin. Methods In this work, we have investigated an ALK inhibitor LDN193189 for its efficacy in iron homeostasis. The effect of LDN193189 treatment was assessed in C57BL6/J mice, in which hepcidin was induced by either ferrous sulfate or lipopolysaccharide (LPS) injection. Results After two hours of treatment, ferrous sulfate increased serum and liver iron, serum hepcidin, and liver hepcidin expression. On the other hand, LPS reduced serum iron in a dose-related manner after six hours of treatment. LDN193189 treatment increased serum iron, decreased spleen and liver iron, decreased serum hepcidin and liver hepcidin expression in ferrous sulfate-treated mice, and increased serum iron in LPS-induced hypoferremia. We observed that ferrous sulfate caused a significantly higher increase in liver iron, serum hepcidin, and liver hepcidin than turpentine oil or LPS in mice. Iron dextran (intraperitoneal or intravenous) increased serum iron, but LDN193189 did not show hyperferremia with iron dextran stimulus. Conclusion Ferrous sulfate-induced hyperferremia can be a valuable and rapid screening model for assessing the efficacy of hepcidin inhibitors.

Hepcidin as a Prospective Individualized Biomarker for Individuals at Risk of Low Energy Availability

2019 ◽  
Vol 29 (6) ◽  
pp. 671-681 ◽  
Author(s):  
Claire E. Badenhorst ◽  
Katherine E. Black ◽  
Wendy J. O’Brien
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Dietary Intervention ◽  
Low Energy ◽  
Energy Availability ◽  
Dietary Interventions ◽  
Hepcidin Expression ◽  
Ketogenic Diets ◽  
Increased Risk ◽  
Low Energy Availability

Hepcidin, a peptide hormone with an acknowledged evolutionary function in iron homeostasis, was discovered at the turn of the 21st century. Since then, the implications of increased hepcidin activity have been investigated as a potential advocate for the increased risk of iron deficiency in various health settings. Such implications are particularly relevant in the sporting community where peaks in hepcidin postexercise (∼3–6 hr) are suggested to reduce iron absorption and recycling, and contribute to the development of exercise-induced iron deficiency in athletes. Over the last decade, hepcidin research in sport has focused on acute and chronic hepcidin activity following single and repeated training blocks. This research has led to investigations examining possible methods to attenuate postexercise hepcidin expression through dietary interventions. The majority of macronutrient dietary interventions have focused on manipulating the carbohydrate content of the diet in an attempt to determine the health of athletes adopting the low-carbohydrate or ketogenic diets, a practice that is a growing trend among endurance athletes. During the process of these macronutrient dietary intervention studies, an observable coincidence of increased cumulative hepcidin activity to low energy availability has emerged. Therefore, this review aims to summarize the existing literature on nutritional interventions on hepcidin activity, thus, highlighting the link of hepcidin to energy availability, while also making a case for the use of hepcidin as an individualized biomarker for low energy availability in males and females.

P1270 SEX HORMONES DIFFERENTLY REGULATE HEPATIC HEPCIDIN EXPRESSION AND SYSTEMIC IRON HOMEOSTASIS IN VIVO

2014 ◽  
Vol 60 (1) ◽  
pp. S512-S513
Author(s):  
C. Garuti ◽  
G. Montosi ◽  
S. Barelli ◽  
A. Pietrangelo ◽  
E. Corradini
Keyword(s):  
Sex Hormones ◽  
Iron Homeostasis ◽  
Hepcidin Expression

scholarly journals Inhibition of bone morphogenetic protein signaling attenuates anemia associated with inflammation

Blood ◽  
2011 ◽  
Vol 117 (18) ◽  
pp. 4915-4923 ◽  
Author(s):  
Andrea U. Steinbicker ◽  
Chetana Sachidanandan ◽  
Ashley J. Vonner ◽  
Rushdia Z. Yusuf ◽  
Donna Y. Deng ◽  
...  
Keyword(s):  
Bone Morphogenetic Protein ◽  
Iron Homeostasis ◽  
Iron Bioavailability ◽  
Bmp Signaling ◽  
Neoplastic Disease ◽  
Type I ◽  
Hepcidin Expression ◽  
Hepatic Expression ◽  
Morphogenetic Protein ◽  
Anemia Of Inflammation

Abstract Anemia of inflammation develops in settings of chronic inflammatory, infectious, or neoplastic disease. In this highly prevalent form of anemia, inflammatory cytokines, including IL-6, stimulate hepatic expression of hepcidin, which negatively regulates iron bioavailability by inactivating ferroportin. Hepcidin is transcriptionally regulated by IL-6 and bone morphogenetic protein (BMP) signaling. We hypothesized that inhibiting BMP signaling can reduce hepcidin expression and ameliorate hypoferremia and anemia associated with inflammation. In human hepatoma cells, IL-6–induced hepcidin expression, an effect that was inhibited by treatment with a BMP type I receptor inhibitor, LDN-193189, or BMP ligand antagonists noggin and ALK3-Fc. In zebrafish, the induction of hepcidin expression by transgenic expression of IL-6 was also reduced by LDN-193189. In mice, treatment with IL-6 or turpentine increased hepcidin expression and reduced serum iron, effects that were inhibited by LDN-193189 or ALK3-Fc. Chronic turpentine treatment led to microcytic anemia, which was prevented by concurrent administration of LDN-193189 or attenuated when LDN-193189 was administered after anemia was established. Our studies support the concept that BMP and IL-6 act together to regulate iron homeostasis and suggest that inhibition of BMP signaling may be an effective strategy for the treatment of anemia of inflammation.

Myocardial iron homeostasis and hepcidin expression in a rat model of heart failure at different levels of dietary iron intake

2019 ◽  
Vol 1863 (4) ◽  
pp. 703-713 ◽  
Author(s):  
Jiri Petrak ◽  
Tereza Havlenova ◽  
Matyas Krijt ◽  
Matej Behounek ◽  
Janka Franekova ◽  
...  
Keyword(s):  
Heart Failure ◽  
Rat Model ◽  
Iron Homeostasis ◽  
Dietary Iron ◽  
Myocardial Iron ◽  
Iron Intake ◽  
Hepcidin Expression ◽  
Different Levels

scholarly journals Dopamine Is a Siderophore-Like Iron Chelator That PromotesSalmonella entericaSerovar Typhimurium Virulence in Mice

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Stefanie Dichtl ◽  
Egon Demetz ◽  
David Haschka ◽  
Piotr Tymoszuk ◽  
Verena Petzer ◽  
...  
Keyword(s):  
Bacterial Growth ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Iron Acquisition ◽  
Lipocalin 2 ◽  
Intracellular Iron ◽  
Content Type ◽  
Hepcidin Expression

ABSTRACTWe have recently shown that the catecholamine dopamine regulates cellular iron homeostasis in macrophages. As iron is an essential nutrient for microbes, and intracellular iron availability affects the growth of intracellular bacteria, we studied whether dopamine administration impacts the course ofSalmonellainfections. Dopamine was found to promote the growth ofSalmonellaboth in culture and within bone marrow-derived macrophages, which was dependent on increased bacterial iron acquisition. Dopamine administration to mice infected withSalmonella entericaserovar Typhimurium resulted in significantly increased bacterial burdens in liver and spleen, as well as reduced survival. The promotion of bacterial growth by dopamine was independent of the siderophore-binding host peptide lipocalin-2. Rather, dopamine enhancement of iron uptake requires both the histidine sensor kinase QseC and bacterial iron transporters, in particular SitABCD, and may also involve the increased expression of bacterial iron uptake genes. Deletion or pharmacological blockade of QseC reduced but did not abolish the growth-promoting effects of dopamine. Dopamine also modulated systemic iron homeostasis by increasing hepcidin expression and depleting macrophages of the iron exporter ferroportin, which enhanced intracellular bacterial growth.Salmonellalacking all central iron uptake pathways failed to benefit from dopamine treatment. These observations are potentially relevant to critically ill patients, in whom the pharmacological administration of catecholamines to improve circulatory performance may exacerbate the course of infection with siderophilic bacteria.IMPORTANCEHere we show that dopamine increases bacterial iron incorporation and promotesSalmonellaTyphimurium growth bothin vitroandin vivo. These observations suggest the potential hazards of pharmacological catecholamine administration in patients with bacterial sepsis but also suggest that the inhibition of bacterial iron acquisition might provide a useful approach to antimicrobial therapy.

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