Caco-2 cell acquisition of dietary iron(III) invokes a nanoparticulate endocytic pathway

Dietary non-heme iron contains ferrous [Fe(II)] and ferric [Fe(III)] iron fractions and the latter should hydrolyze, forming Fe(III) oxo-hydroxide particles, on passing from the acidic stomach to less acidic duodenum. Using conditions to mimic the in vivo hydrolytic environment we confirmed the form...

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Published inPloS one Vol. 8; no. 11; p. e81250
Main Authors Pereira, Dora I A, Mergler, Bianca I, Faria, Nuno, Bruggraber, Sylvaine F A, Aslam, Mohamad F, Poots, Lynsey K, Prassmayer, Laura, Lönnerdal, Bo, Brown, Andy P, Powell, Jonathan J
Format Journal Article
LanguageEnglish
Published United States Public Library of Science 21.11.2013
Public Library of Science (PLoS)
Subjects
Caco-2 Cells
Cell culture
Citric acid
Clathrin
Computer simulation
Councils
Diet
Divalent metal transporter-1
Duodenum
Electron microscopy
Endocytosis
Epithelium
Ferritin
Ferritins - metabolism
Glycoproteins
Heme
Humans
Inhibition
Internalization
Intestine
Iron
Iron, Dietary - metabolism
Laboratories
Ligands
Lysosomes - metabolism
Medical research
Metal Nanoparticles
Molecular weight
Monensin
Nanoparticles
Nanoparticles - chemistry
Nanoparticles - ultrastructure
Nutrition research
Particulates
Proteins
Rodents
Stomach
Transmission electron microscopy
United States > US
California
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Summary:Dietary non-heme iron contains ferrous [Fe(II)] and ferric [Fe(III)] iron fractions and the latter should hydrolyze, forming Fe(III) oxo-hydroxide particles, on passing from the acidic stomach to less acidic duodenum. Using conditions to mimic the in vivo hydrolytic environment we confirmed the formation of nanodisperse fine ferrihydrite-like particles. Synthetic analogues of these (~ 10 nm hydrodynamic diameter) were readily adherent to the cell membrane of differentiated Caco-2 cells and internalization was visualized using transmission electron microscopy. Moreover, Caco-2 exposure to these nanoparticles led to ferritin formation (i.e., iron utilization) by the cells, which, unlike for soluble forms of iron, was reduced (p=0.02) by inhibition of clathrin-mediated endocytosis. Simulated lysosomal digestion indicated that the nanoparticles are readily dissolved under mildly acidic conditions with the lysosomal ligand, citrate. This was confirmed in cell culture as monensin inhibited Caco-2 utilization of iron from this source in a dose dependent fashion (p<0.05) whilet soluble iron was again unaffected. Our findings reveal the possibility of an endocytic pathway for acquisition of dietary Fe(III) by the small intestinal epithelium, which would complement the established DMT-1 pathway for soluble Fe(II).
Bibliography:These authors contribute equally to this work.
Conceived and designed the experiments: DIAP BIM JJP. Performed the experiments: DIAP BIM LKP LP MFA. Analyzed the data: DIAP BIM MFA APB. Contributed reagents/materials/analysis tools: BL NF SFAB APB. Wrote the manuscript: DIAP APB JJP. Developed the hypothesis behind this research: JJP DIAP. Provided input on development of the hypothesis behind this research: SFAB NF APB. Had primary responsibility for final content: DIAP JJP. Read, provided input to and approved the manuscript: DIAP BIM NF SFAB MFA LKP LP BL APB JJP.
Competing Interests: The authors declare no conflict of interest but D.I.A.P., N.F., S.F.A.B. and J.J.P. wish to note that they are inventors on a patent detailing novel Fe(III) poly oxo-hydroxide structures that may have potential as dietary supplements [Powell, J., S. Bruggraber, et al. (2008). Ligand modified poly oxo-hydroxy metal ion materials, their uses and processes for their preparation. W. I. P. Organization, U.K. WO/2008/096130]. This patent does not alter adherence to all PLOS ONE policies on sharing data or materials.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0081250