PMID- 27714044
OWN - NLM
STAT- MEDLINE
DCOM- 20171211
LR  - 20191210
IS  - 1756-591X (Electronic)
IS  - 1756-5901 (Print)
IS  - 1756-5901 (Linking)
VI  - 8
IP  - 9
DP  - 2016 Sep 1
TI  - Knockdown of copper-transporting ATPase 1 (Atp7a) impairs iron flux in 
      fully-differentiated rat (IEC-6) and human (Caco-2) intestinal epithelial cells.
PG  - 963-972
AB  - 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.: Gastrointest. Liver Physiol., 2005, 288, G964-G971). This led us to 
      postulate that Atp7a may influence intestinal iron flux. Therefore, to test the 
      hypothesis that Atp7a is required for optimal iron transport, we silenced Atp7a 
      in rat IEC-6 and human Caco-2 cells. Iron transport was subsequently quantified 
      in fully-differentiated cells plated on collagen-coated, transwell inserts. 
      Interestingly, (59)Fe uptake and efflux were impaired in both cell lines by Atp7a 
      silencing. Concurrent changes in the expression of key iron transport-related 
      genes were also noted in IEC-6 cells. Expression of Dmt1 (the iron importer), 
      Dcytb (an apical membrane ferrireductase) and Fpn1 (the iron exporter) was 
      decreased in Atp7a knockdown (KD) cells. Paradoxically, cell-surface 
      ferrireductase activity increased (>5-fold) in Atp7a KD cells despite decreased 
      Dcytb mRNA expression. Moreover, increased expression (>10-fold) of hephaestin 
      (an iron oxidase involved in iron efflux) was associated with increased 
      ferroxidase activity in KD cells. Increases in ferrireductase and ferroxidase 
      activity may be compensatory responses to increase iron flux. In summary, in 
      these reductionist models of the mammalian intestinal epithelium, Atp7a KD 
      altered expression of iron transporters and impaired iron flux. Since Atp7a is a 
      copper transporter, it is a logical supposition that perturbations in 
      intracellular copper homeostasis underlie the noted biologic changes in these 
      cell lines.
FAU - Ha, Jung-Heun
AU  - Ha JH
AD  - Food Science and Human Nutrition Department, University of Florida, Gainesville, 
      Florida, USA.
FAU - Doguer, Caglar
AU  - Doguer C
AD  - Food Science and Human Nutrition Department, University of Florida, Gainesville, 
      Florida, USA.
FAU - Collins, James F
AU  - Collins JF
AD  - Food Science and Human Nutrition Department, University of Florida, Gainesville, 
      Florida, USA and Food Science & Human Nutrition Department, University of 
      Florida, Gainesville, FL 32611, USA. jfcollins@ufl.edu.
LA  - eng
GR  - R01 DK074867/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PL  - England
TA  - Metallomics
JT  - Metallomics : integrated biometal science
JID - 101478346
RN  - 789U1901C5 (Copper)
RN  - E1UOL152H7 (Iron)
RN  - EC 1.16.3.1 (Ceruloplasmin)
RN  - EC 1.5.1.38 (FMN Reductase)
RN  - EC 1.6.99.- (ferric citrate iron reductase)
RN  - EC 7.2.2.8 (Copper-Transporting ATPases)
SB  - IM
MH  - Animals
MH  - Biological Transport
MH  - *Cell Differentiation
MH  - Cells, Cultured
MH  - Ceruloplasmin/*metabolism
MH  - Copper/*metabolism
MH  - Copper-Transporting ATPases/*antagonists & inhibitors/genetics/metabolism
MH  - FMN Reductase/*metabolism
MH  - Humans
MH  - Intestinal Mucosa/cytology/*metabolism
MH  - Iron/*metabolism
MH  - Rats
PMC - PMC5180600
MID - NIHMS814772
EDAT- 2016/10/08 06:00
MHDA- 2017/12/12 06:00
PMCR- 2017/09/01
CRDT- 2016/10/08 06:00
PHST- 2016/10/08 06:00 [entrez]
PHST- 2016/10/08 06:00 [pubmed]
PHST- 2017/12/12 06:00 [medline]
PHST- 2017/09/01 00:00 [pmc-release]
AID - 10.1039/c6mt00126b [doi]
PST - ppublish
SO  - Metallomics. 2016 Sep 1;8(9):963-972. doi: 10.1039/c6mt00126b.