Hepcidin induces intestinal calcium uptake while suppressing iron uptake in Caco-2 cells

PLoS One. 2021 Oct 13;16(10):e0258433. doi: 10.1371/journal.pone.0258433. eCollection 2021.

Abstract

Abnormal calcium absorption and iron overload from iron hyperabsorption can contribute to osteoporosis as found in several diseases, including hemochromatosis and thalassemia. Previous studies in thalassemic mice showed the positive effects of the iron uptake suppressor, hepcidin, on calcium transport. However, whether this effect could be replicated in other conditions is not known. Therefore, this study aimed to investigate the effects of hepcidin on iron and calcium uptake ability under physiological, iron uptake stimulation and calcium uptake suppression. To investigate the potential mechanism, effects of hepcidin on the expression of iron and calcium transporter and transport-associated protein in Caco-2 cells were also determined. Our results showed that intestinal cell iron uptake was significantly increased by ascorbic acid together with ferric ammonium citrate (FAC), but this phenomenon was suppressed by hepcidin. Interestingly, hepcidin significantly increased calcium uptake under physiological condition but not under iron uptake stimulation. While hepcidin significantly suppressed the expression of iron transporter, it had no effect on calcium transporter expression. This indicated that hepcidin-induced intestinal cell calcium uptake did not occur through the stimulation of calcium transporter expression. On the other hand, 1,25(OH)2D3 effectively induced intestinal cell calcium uptake, but it did not affect intestinal cell iron uptake or iron transporter expression. The 1,25(OH)2D3-induced intestinal cell calcium uptake was abolished by 12 mM CaCl2; however, hepcidin could not rescue intestinal cell calcium uptake suppression by CaCl2. Taken together, our results showed that hepcidin could effectively and concurrently induce intestinal cell calcium uptake while reducing intestinal cell iron uptake under physiological and iron uptake stimulation conditions, suggesting its therapeutic potential for inactive calcium absorption, particularly in thalassemic patients or patients who did not adequately respond to 1,25(OH)2D3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caco-2 Cells
  • Calcitriol / pharmacology
  • Calcium / metabolism*
  • Calcium Chloride / pharmacology
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Hepcidins / pharmacology*
  • Humans
  • Intestinal Mucosa / cytology
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Ion Transport / drug effects*
  • Iron / metabolism*
  • TRPV Cation Channels / genetics
  • TRPV Cation Channels / metabolism
  • Up-Regulation / drug effects

Substances

  • Cation Transport Proteins
  • Hepcidins
  • TRPV Cation Channels
  • TRPV6 channel
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • Iron
  • Calcitriol
  • Calcium Chloride
  • Calcium

Grants and funding

This research project was supported by the CIF and CNI grant, Faculty of Science, Mahidol University (to KL and NC) and Science Achievement Scholarship of Thailand (SAST) (to SP). NC is a NRCT Distinguished Research Professor supported by the National Research Council of Thailand (NRCT)-Mahidol University, Mahidol University-Multidisciplinary Research Cluster Grant, National Science and Technology Development Agency (NSTDA), and Research Assistant Grant, Faculty of Science, Mahidol University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.