Biliary excretion of excess iron in mice requires hepatocyte iron import by Slc39a14

Abstract

Iron is essential for erythropoiesis and other biological processes, but is toxic in excess. Dietary absorption of iron is a highly regulated process and is a major determinant of body iron levels. Iron excretion, however, is considered a passive, unregulated process, and the underlying pathways are unknown. Here we investigated the role of metal transporters SLC39A14 and SLC30A10 in biliary iron excretion. While SLC39A14 imports manganese into the liver and other organs under physiological conditions, it imports iron under conditions of iron excess. SLC30A10 exports manganese from hepatocytes into the bile. We hypothesized that biliary excretion of excess iron would be impaired by SLC39A14 and SLC30A10 deficiency. We therefore analyzed biliary iron excretion in Slc39a14 -and Slc30a10 -deficient mice raised on iron-sufficient and -rich diets. Bile was collected surgically from the mice, then analyzed with nonheme iron assays, mass spectrometry, ELISAs, and an electrophoretic assay for iron-loaded ferritin. Our results support a model in which biliary excretion of excess iron requires iron import into hepatocytes by SLC39A14, followed by iron export into the bile predominantly as ferritin, with iron export occurring independently of SLC30A10. To our knowledge, this is the first report of a molecular determinant of mammalian iron excretion and can serve as basis for future investigations into mechanisms of iron excretion and relevance to iron homeostasis.

Iron Metabolism in Cardiovascular Disease: Physiology, Mechanisms, and Therapeutic Targets

“…9,10 Physiologically, most of the iron that leaves the body is lost through menstruation in women or sloughing of epithelial-lined surfaces such as the skin, intestinal mucosa, urinary and biliary tracts. [11][12][13] There are no known regulated pathways for active iron excretion; therefore, maintaining systemic and intracellular iron homeostasis is largely dependent on absorption. 14…”

Role of excretion in manganese homeostasis and neurotoxicity: a historical perspective

“…Since SLC39A14 and SLC39A8 are metal importers with a broader substrate specificity compared with SLC30A10, these studies are expected to provide insights beyond Mn excretion and into areas such as the transport of Mn across the bloodbrain barrier (95), as well as into neurons and glia, homeostatic control of other metals (e.g., SLC39A14 was recently reported to play a role in biliary excretion of excess iron; Ref. 96), and biology of other disease conditions (e.g., association of SLC39A8 missense mutation with Crohn's disease; Ref. 97).…”

Safety and efficacy of a novel iron chelator (HBED; (N,N′‐Di(2‐hydroxybenzyl)ethylenediamine‐N,N′‐diacetic acid)) in equine (Equus caballus) as a model for black rhinoceros (Diceros bicornis)

“…In contrast to all other minerals, iron cannot be actively regulated to be excreted from the body. While recent studies have documented biliary excretion of iron in genetically iron loaded knockout mice models (Mercadante et al, 2019; Prajapati et al, 2021), that has not been demonstrated as an active mechanism of iron regulation in other species, especially non‐iron loaded species such as the horse. The level of iron in the body is primarily regulated via absorption in the small intestine at the brush‐border membrane of duodenal enterocytes.…”