
James F CollinsUniversity of Florida | UF · Department of Food Science and Human Nutrition
James F Collins
PhD
https://fshn.ifas.ufl.edu/about/faculty-bio-pages/collins/collins-lab/
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224
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Introduction
Publications
Publications (224)
β-thalassemia is an iron-loading anemia caused by homozygous mutation of the hemoglobin subunit β (HBB) gene. In β-thalassemia intermedia (βTI), a non-transfusion-dependent form of the disease, iron overload is caused by excessive absorption of dietary iron due to inappropriately low production of the iron-regulatory hormone hepcidin. Low hepcidin...
Iron plays a crucial role in many physiological processes, including oxygen transport, bioenergetics, and immune function. Iron is assimilated from food and also recycled from senescent red blood cells. Iron exists in two dietary forms: heme (animal based) and non-heme (mostly plant based). The body uses iron for metabolic purposes, and stores the...
Iron deficiency (ID) and iron‐deficiency anaemia (IDA) are global public health concerns, most commonly afflicting children, pregnant women and women of childbearing age. Pathological outcomes of ID include delayed cognitive development in children, adverse pregnancy outcomes and decreased work capacity in adults. IDA is usually treated by oral iro...
Assessing gastrointestinal motility lacks simultaneous evaluation of intraluminal pressure (ILP), circular muscle (CM) and longitudinal muscle (LM) contraction, and lumen emptying. In this study, a sophisticated machine was developed that synchronized real-time recordings to quantify the intricate interplay between CM and LM contractions, and their...
Pregnancy rates in β-thalassemia are increasing, but the risk of complications is higher; thus, better understanding of maternal and fetal iron homeostasis in this disorder is needed. HbbTh3/+ (Th3/+) mice model human β-thalassemia. Both the murine and human diseases are characterized by low hepcidin, high iron absorption and tissue iron overload,...
Adipose plasticity is critical for metabolic homeostasis. Adipocyte transdifferentiation plays an important role in adipose plasticity, but the molecular mechanism of transdifferentiation remains incompletely understood. Here we show that the transcription factor FoxO1 regulates adipose transdifferentiation by mediating Tgfβ1 signaling pathway. Tgf...
Heme iron, derived from hemoglobin and myoglobin of animal products, is efficiently absorbed and utilized by humans. Despite extensive investigation over the last several decades, the exact mechanism(s) of heme-iron absorption and tissue utilization of absorbed heme are unclear. Mice are frequently used for investigation of iron biology; however, m...
Iron (Fe) and Copper (Cu) are essential trace minerals that are important in various biological processes within the body. High iron intake has been associated with perturbations in copper metabolism leading to copper deficiency in rats and mice. We hypothesized that high dietary iron blocks intestinal copper transport via the divalent metal transp...
The established iron requirement for laboratory rodents is 35-50 ppm, but standard rodent chows contain up to 350 ppm iron. Excess dietary iron exacerbates iron accumulation in hepcidin (Hamp) knockout (KO) mice and rats, which model the iron-overload disorder hereditary hemochromatosis (HH) in humans. Establishing iron requirements is important to...
β-thalassemia intermedia (βTI) is characterized by chronic anemia, ineffective erythropoiesis, and excessive intestinal iron absorption leading to systemic iron overload. Divalent metal-ion transporter 1 (DMT1), the main intestinal iron transporter, may mediate excessive iron absorption in Th3/+ mice, which model βTI.
Objective:
To determine if i...
The mammalian multicopper ferroxidases (MCFs) ceruloplasmin (CP), hephaestin (HEPH) and zyklopen (ZP) comprise a family of conserved enzymes that are essential for body iron homeostasis. Each of these enzymes contains six biosynthetically incorporated copper atoms which act as intermediate electron acceptors, and the oxidation of iron is associated...
Iron-deficiency anemia is common worldwide and typically treated by oral iron supplementation. Excess enteral iron, however, may cause pathological outcomes. Developing new repletion approaches is thus warranted. Previous experimentation revealed that select amino acids (AAs) induce trafficking of transporters onto the enterocyte brush-border membr...
Mucosal damage, barrier breach, inflammation, and iron-deficiency anemia (IDA) typify ulcerative colitis (UC) in humans. The anemia in UC appears to mainly relate to systemic inflammation. The pathogenesis of this ‘anemia of inflammation’ (AI) involves cytokine-mediated transactivation of hepatic Hamp (encoding the iron-regulatory hormone, hepcidin...
Intestinal iron transport requires an iron importer (Dmt1) and an iron exporter (Fpn1). The hormone hepcidin regulates iron absorption by modulating Fpn1 protein levels on the basolateral surface of duodenal enterocytes. In the genetic, iron-loading disorder hereditary hemochromatosis (HH), hepcidin production is low and Fpn1 protein expression is...
The essential trace mineral copper plays important roles in human physiology and pathophysiology. Disruption of copper homeostasis may underlie the development of ischemic heart disease, and connective tissue and neurodegenerative disorders. Copper also likely participates in the host response to bacterial infection and is further implicated more b...
Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high dietary ir...
The nicotianamine-iron chelate [NA-Fe²⁺], which is found in many plant-based foods, has been recently described as a new form of bioavailable iron in mice and chickens. How NA-Fe²⁺ is assimilated from the diet, however, remains unclear. The current investigation by Murata et al. has identified the proton-coupled amino acid transporter 1 (PAT1) as t...
Synthetic nanoparticle-based drug delivery system is widely known for its ability to increase the efficacy and specificity of loaded drugs, but it often suffers from relatively higher immunotoxicity and higher costs as compared to traditional drug formulations. Contrarily, plant-derived nanoparticles appear to be free from these limitations of synt...
Abstract
Iron deficiency (ID), usually due to excessive menstrual bleeding, rapid neonatal and adolescent growth, pregnancy or gastric bypass, is quite common in the U.S. Iron overload (IO) also afflicts thousands of individuals in America, being most frequently associated with Hereditary Hemochromatosis (HH) and β-thalassemia. Treatment of ID with...
Beta‐thalassemia is a disease associated with decreased β‐globin production due to mutations in the β‐globin gene and characterized by chronic anemia, ineffective erythropoiesis, low hepcidin levels, and systemic iron overload. In β‐thalassemia intermedia, some β‐globin is still produced, preventing the need for regular blood transfusions. These pa...
Intensive research over the past several years has demonstrated (or predicted) that pathological perturbations in copper homeostasis may contribute to the development of ischemic heart disease and neurodegenerative and connective tissue disorders in humans. Copper was also shown to facilitate the host response to bacterial infection. Emerging evide...
Hinokitiol, a natural lipophilic chelator, appears capable of replacing several iron transporters after they have been genetically ablated. Divalent metal-ion transporter (DMT1) is the major iron importer in enterocytes and erythroblasts. We have compared DMT1 and hinokitiol in multiple fashions to learn if the smaller molecule is a suitable substi...
Research on the interplay between iron and copper metabolism in humans began to flourish in the mid-20th century, and diseases associated with dysregulated homeostasis of these essential trace minerals are common even today. Iron deficiency is the most frequent cause of anemia worldwide, leading to significant morbidity, particularly in developing...
Introduction
Inappropriately increased intestinal iron absorption, leading to pathologic tissue iron accumulation, typifies a group of iron‐loading disorders collectively referred to as hereditary hemochromatosis (HH). HH is caused by genetic mutations that lead to inappropriately low (or absent) production of the iron‐regulatory hormone hepcidin,...
Introduction
The chronic anemia associated with IBD in humans may result from trans‐ activation of the the iron‐regulatory hormone ( Hamp ) by pro‐inflammatory cytokines in hepatocytes. High hepcidin decreases serum iron by blunting intestinal iron absorption and impairing release of storage iron, thus decreasing iron delivery to the erythroid marr...
Approximately 1.6 billion people worldwide are anemic, with iron deficiency (ID) as the most common cause. Moreover, iron overload (IO), most commonly associated with the genetic disease Hereditary Hemochromatosis (HH), affects some 1 million individuals in the US. Both conditions warrant better treatment options, as iron supplementation is not alw...
Nanoparticles (NPs) have been utilized to deliver drugs to the intestinal epithelium in vivo. Moreover, NPs derived from edible plants are less toxic than synthetic NPs. Here, we utilized ginger NP-derived lipid vectors (GDLVs) in a proof-of-concept investigation to test the hypothesis that inhibiting expression of divalent metal-ion transporter 1...
High‐iron feeding (1–2% Fe) is a commonly used approach to induce iron overload in rodents, modeling genetic iron‐loading disorders in humans. We recently utilized this approach to create a rat model of iron overload. To our surprise though, high dietary iron (0.8%; 8800 ppm) consumption impaired growth and caused copper‐deficiency anemia and cardi...
Genetically‐modified mouse models of altered iron homeostasis have made invaluable contributions to our understanding of the regulation of iron metabolism in humans. Emerging evidence, however, suggests that mice may not be the best model for all aspects of human physiology/pathophysiology. For example, mice display a resistance to liver cirrhosis...
Introduction
Iron and copper homeostasis is intimately intertwined. This is not surprising given the similar physiochemical and toxicological properties of the two redox‐active metals. Previous studies showed that copper accumulates in tissues important for iron homeostasis during iron deprivation (e.g. the intestinal mucosa, liver, blood). Also, t...
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...
Background:
Divalent metal-ion transporter 1 (DMT1) may transport copper, but studies to date on this topic have been equivocal. Previously, an ex vivo experiment showed that intestinal copper transport was impaired in Dmt1-mutant Belgrade rats.
Objective:
In this study, we tested the hypothesis that intestinal DMT1 transports copper in vivo.
M...
Dietary iron overload in rodents impairs growth and causes cardiac hypertrophy, serum and tissue copper depletion, depression of serum ceruloplasmin (Cp) activity and anemia. Notably, increasing dietary copper content to ~25-fold above requirements prevents the development of these physiological perturbations. Whether copper supplementation can rev...
Our previous studies showed that high‐iron (0.88% carbonyl iron) diet feeding of mice and rats lead to impaired growth, severe anemia, tissue copper depletion and cardiac hypertrophy. 1,2 Interestingly, these pathophysiological perturbations were prevented by addition of extra copper to the high Fe diet, indicating the role of copper deficiency in...
Iron derived from dietary sources is essential to support numerous physiological functions in mammals, including oxygen transport, energy production, antioxidant defense, and regulation of gene expression. Absorption of dietary iron in the proximal small intestine is a highly regulated, dynamic process, representing a crucial step in overall body i...
Background
Consumption of a high-iron diet causes copper deficiency in weanling rodents; however, the minimum amount of dietary iron that disrupts copper homeostasis has not been established.
Objective
We tested the hypothesis that dietary iron at only several-fold above physiologic requirements would cause copper depletion.
Methods
Weanling male...
Key Points
Intestinal Heph may be required to potentiate iron absorption during rapid growth and pregnancy, or when hypoxia stimulates erythropoiesis. Here, the physiological conditions in which Heph is required are defined and other, complementary, intestinal ferroxidases are identified.
Aim:
To develop novel siRNA delivery system overcoming the limitations of synthetic nanoparticles, such as potential side effects, nonspecificity and economic production for ulcerative colitis therapy.
Materials & methods:
Nanoparticles composed of edible ginger-derived lipid, termed ginger-derived lipid vehicles (GDLVs) were generated from ging...
High-iron feeding of rodents has been commonly used to model human iron-overload disorders. We recently noted that high-iron consumption impaired growth and caused severe systemic copper deficiency in growing rats, but the mechanism by which this occurred could not be determined due to technical limitations. In the current investigation, we thus ut...
Copper is an essential dietary nutrient for humans and other mammalian species. Consistent with its definition as a trace mineral, human tissues and body fluids contain copper at concentrations in the microgram per gram (i.e., parts per million) to the nanogram per gram (i.e., parts per billion) range. It is also now clear that high or low body cop...
Intestinal iron absorption is highly regulated since no mechanism for iron excretion exists. We previously demonstrated that expression of an intestinal copper transporter (Atp7a) increases in parallel with genes encoding iron transporters in the rat duodenal epithelium during iron deprivation (Am J Physiol GI/Liv Physiol. 288:G964-71, 2005). This...
Iron-copper interactions were described decades ago; however, molecular mechanisms linking the two essential minerals remain largely undefined. Investigations in humans and other mammals noted that copper levels increase in the intestinal mucosa, liver and blood during iron deficiency, tissues all important for iron homeostasis. The current study w...
Introduction: Human colonic carcinoma (Caco-2) cells are a well-established model of the human intestinal epithelium. When grown in post-confluent culture, they take on a small intestinal epithelial cell-like phenotype. This model system was utilized to test the hypothesis that mineral/amino acid chelates will have better bioavailability than miner...
The interrelationships between iron and copper metabolism have been recognized for decades. Two multi-copper ferroxidases (FOXs), hephaestin (HEPH) and ceruloplasmin (CP), are the best-identified links between iron and copper homeostasis. These FOXs are required for efflux of dietary iron from duodenal enterocytes (HEPH and possibly CP), and for ef...
A commonly used method to cause iron loading in rodents is feeding of a 1-2% carbonyl iron diet. This high amount of dietary iron presumably bypasses normal protective mechanisms and leads to increased body iron levels. We utilized this dietary iron-overload model in a mouse feeding study in which we also altered the dietary copper content. This st...
Introduction: Iron-copper interactions in humans were reported more than a century ago; however, the molecular mechanism(s) underlying the link between iron absorption and copper status are just beginning to be understood. Although absorption of these two metals is closely related, copper status in iron-deficient and iron-overload rodent models has...
Introduction: Recent studies demonstrated that iron and copper homeostasis are intimately intertwined. This is perhaps not surprising given the similar physiochemical properties of the two redox-active metals. Our recent studies provided evidence that copper influences intestinal iron absorption. In particular, we demonstrated that the main intesti...
Introduction
Humans have no regulated means to rid the body of excess iron. Overall body iron levels are thus determined by intestinal iron absorption. Absorption of non‐heme, ferric iron by duodenal enterocytes requires enzymatic reduction and subsequent import by DMT1. Ferrous iron is then exported by the basolateral iron transporter FPN1. After...
Introduction
Iron‐copper interactions in humans were reported more than a century ago; however, the molecular mechanism(s) underlying the link between iron absorption and copper status are just beginning to be understood. Although absorption of these two metals is closely related, copper status in iron‐deficient and iron‐overload rodent models has...
Introduction
Human colonic carcinoma (Caco‐2) cells are a well‐established model of the human intestinal epithelium. When grown in post‐confluent culture, they take on a small intestinal epithelial cell‐like phenotype. This model system was utilized to test the hypothesis that mineral/amino acid chelates will have better bioavailability than minera...
A commonly used method to cause iron loading in rodents is feeding of a 1–2% carbonyl iron diet. This high amount of dietary iron presumably bypasses normal protective mechanisms and leads to increased body iron levels. We utilized this dietary iron‐overload model in a mouse feeding study in which we also altered the dietary copper content. This st...
Introduction
Recent studies demonstrated that iron and copper homeostasis are intimately intertwined. This is perhaps not surprising given the similar physiochemical properties of the two redox‐active metals. Our recent studies provided evidence that copper influences intestinal iron absorption. In particular, we demonstrated that the main intestin...
A common method to cause iron loading in rodents is feeding a high-iron diet, which presumably bypasses normal
protective mechanisms (e.g. a block to absorption or storage in ferritin) and leads to increased body iron levels. We
utilized this dietary iron-overload model in a mouse feeding study in which we also altered the dietary copper content. T...
Intestinal iron absorption is tightly regulated since no active excretory pathways for iron exist in mammals. Iron homeostasis isintertwined withthat of copper (Cu), but specific molecular interactions are yet to be defined. To further evaluate iron‐copper interplay in the mammalian intestine, low, control, or high‐iron diets (3, 50and 10,000 ppm,...
Hephaestin (HEPH) is an intestinal ferroxidase (FOX) that has been implicated as essential for intestinal iron absorption. HEPH oxidizes ferrous iron exported by ferroportin 1, to allow binding of ferric iron to transferrin in the blood. We have previously discovered: 1) the existence of a soluble, intracellular form of HEPH, and 2) that additional...
The Menkes copper-transporting ATPase (Atp7a) has dual roles in mammalian enterocytes: pumping copper into the trans-Golgi network (to support cuproenzyme synthesis) and across the basolateral membrane (to deliver dietary copper to the blood). Atp7a is strongly induced in the rodent duodenum during iron deprivation, suggesting that copper influence...
Iron is an essential trace mineral that plays a number of important physiologic roles in humans, including oxygen transport, energy metabolism and neurotransmitter synthesis. Iron absorption by the proximal small bowel is a critical check point in the maintenance of whole-body iron levels as, unlike most other essential nutrients, no regulated excr...
Absorption of non-heme iron in the mammalian duodenum requires an oxidase so that ferrous iron exported by ferroportin (FPN) can be converted to the ferric state to allow binding to transferrin in the interstitial fluids. Hephaestin (HEPH) represents the only intestinal ferroxidase (FOX) identified to date, but recent reports have suggested that ad...
Intestinal transport of inorganic iron has been intensively studied. Ferric iron is reduced, possibly by duodenal cytochrome b (Dcytb), and transported into cells by divalent metal-ion transport 1 (Dmt1). Ferrous iron is exported from enterocytes via ferroportin 1 (Fpn1) and is then oxidized prior to binding to transferrin. The efflux step, involvi...
Intestinal transport of inorganic iron has been intensively studied. Ferric iron is reduced, possibly by duodenal cytochrome b (Dcytb), and transported into cells by divalent metal‐ion transport 1 (Dmt1). Ferrous iron is exported from enterocytes via ferroportin 1 (Fpn1) and is then oxidized prior to binding to transferrin. The efflux step, involvi...
The Menkes copper-transporting ATPase (Atp7a) gene is induced in rat duodenum during iron deficiency, consistent with copper accumulation in the intestinal mucosa and liver. To test the hypothesis that ATP7A influences intestinal iron metabolism, the Atp7a gene was silenced in rat intestinal epithelial (IEC-6) cells using short hairpin RNA (shRNA)...
Intracellular copper-binding proteins (metallothionein I/II) and a copper exporter (Menkes copper-transporting ATPase) are upregulated in duodenal enterocytes from iron-deficient rats, consistent with copper accumulation in the intestinal mucosa. How copper enters enterocytes during iron deficiency is, however, not clear. Divalent metal transporter...
Genes with G/C-rich promoters were up-regulated in the duodenal epithelium of iron-deficient rats including those encoding
iron (e.g. Dmt1 and Dcytb) and copper (e.g. Atp7a and Mt1) metabolism-related proteins. It was shown previously that an intestinal copper transporter (Atp7a) was co-regulated with iron transport-related genes by a hypoxia-induc...
During iron deficiency, perturbations in copper homeostasis have frequently been documented. Previous studies in iron-deprived rats demonstrated that enterocyte and hepatic copper levels increase and a copper transporter (the Menkes Copper ATPase; Atp7a) is induced in the duodenal epithelium in parallel to iron transport-related genes (e.g. Dmt1, D...
Relative Cp activity as a function of serum and liver copper levels. Plots show the relationship between serum (A) and liver (B) copper and Cp activity. Lines fitting the data were derived by linear regression for Cp activity versus serum and liver copper. In panels A and B, P<0.0001. r, Pearson correlation coefficient.
(TIF)
Sequences of Oligonucleotide Primers Used for qRT-PCR Analysis. Forward (F) and reverse (R) primers used for PCR analysis of gene expression are listed. Cyclophilin was utilized as an internal standard for normalization of experimental gene expression.
(TIF)
Summary of Iron- and Copper-Related Parameters in Experimental Mice. A summary of all data obtained in this investigation is listed. Parameters that were not different between groups are shaded blue. Yellow shading indicates an increase in this parameter as compared to WT mice. Fold increases were estimated by averaging the values from increased gr...