Heme carrier protein 1 transports heme and is involved in heme-Fe metabolism

Abstract

Heme-Fe is an important source of dietary iron in humans; however, the mechanism for heme-Fe uptake by enterocytes is poorly understood. Heme carrier protein 1 (HCP1) was originally identified as mediating heme-Fe transport although it later emerged that it was a folate transporter. We asked what happened to heme-Fe and folate uptake and the relative abundance of hcp1 and ho1 mRNA in Caco-2 cells after knockdown by transfection with HCP1-directed short hairpin (sh)RNA. Control Caco-2 cells were cultured in bicameral chambers with 0-80 μM heme-Fe for selected times. Intracellular Fe and heme concentration increased in Caco-2 cells reflecting higher external heme-Fe concentrations. Maximum Fe, heme, and heme oxygenase 1 (HO1) expression and activity were observed between 12 and 24 h of incubation. Quantitative RT-PCR for hcp1 revealed that its mRNA decreased at 20 μM heme-Fe while ho1 mRNA and activity increased. When shRNA knocked down hcp1 mRNA, heme-(55)Fe uptake and [(3)H]folate transport mirrored the mRNA decrease, ho1 mRNA increased, and flvcr mRNA was unchanged. These data argue that HCP1 is involved in low-affinity heme-Fe uptake not just in folate transport.

Physiology of Iron Metabolism

“…Most heme is absorbed in the proximal intestine, with absorptive capacity decreasing distally, and the role of specific proteins such as hephaestin has been deciphered [84,85]. HCP1, which presents homology to bacterial metal-tetracycline transporters, mediates heme uptake by the cells at the luminal brush border membrane of duodenal enterocytes.…”

‘Ride on the ferrous wheel’ – The cycle of iron in macrophages in health and disease

“…It co-localizes with Hb-Hp complexes, Tf and Dmt1 in early endosomes and may contribute to receptor-mediated endocytosis of Hb-Hp complexes (Schaer et al, 2008). Given that Hcp1 has later been found to transport folate more efficiently than free heme, these results may require further investigation although low-affinity heme transport by Hcp1 could be confirmed independently (Le Blanc et al, 2012).…”

Hepcidin in Iron Homeostasis: Diagnostic and Therapeutic Implications in Type 2 Diabetes Mellitus Patients

“…After reduction on the apical surface of the enterocytes, it enters the cell by divalent metal transporter-1 (DMT1) mediated by an inward proton gradient. Heme is also absorbed by a recently identified receptor called heme carrier protein (HCP1) and catalyzed by heme oxygenase-1 (HO-1) to liberate Fe 2+ [10,11,12,13]. …”