Duodenal Cytochrome b (DCYTB) in Iron Metabolism: An Update on Function and Regulation

Lane, Darius J.R.; Bae, Dong-Hun; Merlot, Angelica M.; Sahni, Sumit; Richardson, Des R.

doi:10.3390/nu7042274

Cited by 113 publications

(89 citation statements)

References 140 publications

(266 reference statements)

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“…Cellular iron is stored in the intracellular iron storage protein, ferritin, in order to both maintain large amounts of iron in a compact and bioavailable form in solution and protect the cell from oxidative damage 70 . Ferrous iron that reaches the basolateral membrane is oxidized back to ferric iron by the trans-membrane ferroxidase, hephaestin (HEPH), and then transported into the circulation by the iron export protein, ferroportin (FPN1), which co-localizes with HEPH in the basolateral membrane 65,67,68 . Dcytb, DMT1, HEPH, and FPN1 were downregulated in response to chronic medium and high doses of TiO 2 with 58 Fe (Figure 4C).…”

Section: Discussionmentioning

confidence: 99%

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

et al. 2017

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Ingestion of titanium dioxide (TiO2) nanoparticles from products such as agricultural chemicals, processed food, and nutritional supplements is nearly unavoidable. The gastrointestinal tract serves as a critical interface between the body and the external environment, and is the site of essential nutrient absorption. The goal of this study was to examine the effects of ingesting the 30 nm TiO2 nanoparticles with an in vitro cell culture model of the small intestinal epithelium, and to determine how acute or chronic exposure to nano-TiO2 influences intestinal barrier function, reactive oxygen species generation, proinflammatory signaling, nutrient absorption (iron, zinc, fatty acids), and brush border membrane enzyme function (intestinal alkaline phosphatase). A Caco-2/HT29-MTX cell culture model was exposed to physiologically relevant doses of TiO2 nanoparticles for acute (four hours) or chronic (five days) time periods. Exposure to TiO2 nanoparticles significantly decreased intestinal barrier function following chronic exposure. Reactive oxygen species (ROS) generation, proinflammatory signaling, and intestinal alkaline phosphatase activity all showed increases in response to nano-TiO2. Iron, zinc, and fatty acid transport were significantly decreased following exposure to TiO2 nanoparticles. This is because nanoparticle exposure induced a decrease in absorptive microvilli in the intestinal epithelial cells. Nutrient transporter protein gene expression was also altered, suggesting that cells are working to regulate the transport mechanisms disturbed by nanoparticle ingestion. Overall, these results show that intestinal epithelial cells are affected at a functional level by physiologically relevant exposure to nanoparticles commonly ingested from food.

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Section: Discussionmentioning

confidence: 99%

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

et al. 2017

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“…Biochemical approaches led to the prediction that a BBM-associated ferric reductase (or “ferrireductase”) existed (244, 310). Subsequently, a transmembrane ferrireductase, called DCYTB, was identified (164, 194). DCYTB reduces iron in vitro and immunological techniques showed that inhibiting DCYTB activity impaired iron reduction in duodenal samples.…”

Section: Intestinal Iron Transport: Detailed Mechanistic Descriptionmentioning

confidence: 99%

“…DCYTB reduces iron in vitro and immunological techniques showed that inhibiting DCYTB activity impaired iron reduction in duodenal samples. Recent studies also showed that intracellular ascorbate provides the reducing equivalents (i.e., electrons) to DCYTB to allow conversion of Fe 3+ to Fe 2+ (164, 315). DCYTB is most robustly expressed in the proximal small intestine, and expression is enhanced by ID and hypoxia (168,194), known stimulators of iron absorption.…”

Section: Intestinal Iron Transport: Detailed Mechanistic Descriptionmentioning

confidence: 99%

Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

Doguer

Collins

2018

Comprehensive Physiology

121

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Iron and copper have similar physiochemical properties; thus, physiologically relevant interactions seem likely. Indeed, points of intersection between these two essential trace minerals have been recognized for many decades, but mechanistic details have been lacking. Investigations in recent years have revealed that copper may positively influence iron homeostasis, and also that iron may antagonize copper metabolism. For example, when body iron stores are low, copper is apparently redistributed to tissues important for regulating iron balance, including enterocytes of upper small bowel, the liver, and blood. Copper in enterocytes may positively influence iron transport, and hepatic copper may enhance biosynthesis of a circulating ferroxidase, ceruloplasmin, which potentiates iron release from stores. Moreover, many intestinal genes related to iron absorption are transactivated by a hypoxia-inducible transcription factor, hypoxia-inducible factor-2α (HIF2α), during iron deficiency. Interestingly, copper influences the DNA-binding activity of the HIF factors, thus further exemplifying how copper may modulate intestinal iron homeostasis. Copper may also alter the activity of the iron-regulatory hormone hepcidin. Furthermore, copper depletion has been noted in iron-loading disorders, such as hereditary hemochromatosis. Copper depletion may also be caused by high-dose iron supplementation, raising concerns particularly in pregnancy when iron supplementation is widely recommended. This review will cover the basic physiology of intestinal iron and copper absorption as well as the metabolism of these minerals in the liver. Also considered in detail will be current experimental work in this field, with a focus on molecular aspects of intestinal and hepatic iron-copper interplay and how this relates to various disease states. © 2018 American Physiological Society. Compr Physiol 8:1433-1461, 2018.

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“…In these experiments, Fe–ascorbate was preferred over Fe–NTA, to avoid a possible interference of Dcytb ferrireductase with the uptake process [37]. The apical iron uptake was considered as the 55 Fe in the cells plus 55 Fe in the basolateral medium after incubation.…”

Section: Methodsmentioning

confidence: 99%

Mathematical Modeling of Intestinal Iron Absorption Using Genetic Programming

et al. 2017

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Iron is a trace metal, key for the development of living organisms. Its absorption process is complex and highly regulated at the transcriptional, translational and systemic levels. Recently, the internalization of the DMT1 transporter has been proposed as an additional regulatory mechanism at the intestinal level, associated to the mucosal block phenomenon. The short-term effect of iron exposure in apical uptake and initial absorption rates was studied in Caco-2 cells at different apical iron concentrations, using both an experimental approach and a mathematical modeling framework. This is the first report of short-term studies for this system. A non-linear behavior in the apical uptake dynamics was observed, which does not follow the classic saturation dynamics of traditional biochemical models. We propose a method for developing mathematical models for complex systems, based on a genetic programming algorithm. The algorithm is aimed at obtaining models with a high predictive capacity, and considers an additional parameter fitting stage and an additional Jackknife stage for estimating the generalization error. We developed a model for the iron uptake system with a higher predictive capacity than classic biochemical models. This was observed both with the apical uptake dataset used for generating the model and with an independent initial rates dataset used to test the predictive capacity of the model. The model obtained is a function of time and the initial apical iron concentration, with a linear component that captures the global tendency of the system, and a non-linear component that can be associated to the movement of DMT1 transporters. The model presented in this paper allows the detailed analysis, interpretation of experimental data, and identification of key relevant components for this complex biological process. This general method holds great potential for application to the elucidation of biological mechanisms and their key components in other complex systems.

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Duodenal Cytochrome b (DCYTB) in Iron Metabolism: An Update on Function and Regulation

Cited by 113 publications

References 140 publications

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

Titanium dioxide nanoparticle ingestion alters nutrient absorption in an in vitro model of the small intestine

Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

Mathematical Modeling of Intestinal Iron Absorption Using Genetic Programming

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