Gum Arabic-Derived Hydroxyproline-Rich Peptides Stimulate
Intestinal Nonheme Iron Absorption via HIF2α-Dependent Upregulation
of Iron Transport Proteins
The
stimulation of host iron absorption is a promising antianemia
strategy adjunctive/alternative to iron intervention. Here, gum arabic
(GA) containing 3.14 ± 0.56% hydroxyproline-rich protein with
repetitive X-(Pro/Hyp)n motifs was found
to increase iron reduction, uptake, and transport to upregulate duodenal
cytochrome b (Dcytb), divalent metal transporter
1 (DMT1), ferroportin, and hephaestin to inhibit hypoxia-inducible
factor (HIF) prolyl hydroxylase (PHD) and to stabilize HIF2α
in polarized Caco-2 cell monolayers in a dose-dependent manner, and
this was dependent on its protein fraction, rather than the polysaccharide
fraction. Three abundant GA-derived hydroxyproline-containing dipeptides
of Hyp–Hyp, Pro–Hyp, and Ser–Hyp were detected
by liquid chromatography-mass spectrometry in the lysates of polarized
Caco-2 cell monolayers at the maximum levels of 0.167 ±
0.021, 0.134 ± 0.017, and 0.089 ± 0.015 μg/mg of protein,
respectively, and showed desirable docking affinity energy values
of −7.53, – 7.91, and −7.39 kcal/mol, respectively,
against human PHD3. GA-derived peptides also acutely increased duodenal
HIF2α stability and Dcytb, DMT1, ferroportin, and hephaestin
transcription in rats (P < 0.05). Overall, GA-derived
hydroxyproline-rich peptides stimulated intestinal iron absorption
via PHD inhibition, HIF2α stabilization, and subsequent upregulation
of iron transport proteins.