Effects of GlyT1 inhibition on erythropoiesis and iron homeostasis in rats

Abstract Glycine is a key rate-limiting component of heme biosynthesis in erythropoietic cells where the high intracellular glycine demand is primarily supplied by the glycine transporter 1 (GlyT1). The impact of intracellular glycine restriction following GlyT1 inhibition on hematopoiesis and iron...

Full description

Saved in:
Bibliographic Details
Published in:Experimental hematology 2016-10, Vol.44 (10), p.964-974.e4
Main Authors: Winter, Michael, Funk, Jürgen, Körner, Annette, Alberati, Daniela, Christen, Francois, Schmitt, Georg, Altmann, Bernd, Pospischil, Andreas, Singer, Thomas
Format: Article
Language:English
Subjects:
Advanced Basic Science
Anemia, Hypochromic - blood
Anemia, Hypochromic - etiology
Anemia, Hypochromic - metabolism
Animals
Biomarkers
Blood Cells - metabolism
Bone Marrow - metabolism
Erythrocyte Inclusions - metabolism
Erythrocyte Inclusions - pathology
Erythrocyte Inclusions - ultrastructure
Erythrocytes, Abnormal - metabolism
Erythrocytes, Abnormal - pathology
Erythrocytes, Abnormal - ultrastructure
Erythropoiesis - drug effects
Female
Ferritins - metabolism
Glycine Plasma Membrane Transport Proteins - antagonists & inhibitors
Hematology, Oncology and Palliative Medicine
Hepcidins - metabolism
Homeostasis - drug effects
Iron - metabolism
Piperazines - adverse effects
Piperazines - pharmacology
Protoporphyrins - metabolism
Rats
Reticulocytes - metabolism
Sulfones - adverse effects
Sulfones - pharmacology
Transferrin - metabolism
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Abstract Glycine is a key rate-limiting component of heme biosynthesis in erythropoietic cells where the high intracellular glycine demand is primarily supplied by the glycine transporter 1 (GlyT1). The impact of intracellular glycine restriction following GlyT1 inhibition on hematopoiesis and iron regulation is not well established. We investigated the effects of a potent and selective inhibitor of GlyT1, bitopertin, on erythropoiesis and iron homeostasis in rats. GlyT1 inhibition significantly affected erythroid heme biosynthesis, manifesting as microcytic hypochromic regenerative anemia with a 20% steady-state reduction in hemoglobin. Reduced erythropoietic iron utilization was characterized by down-regulation of the transferrin receptor 1 (TfR1) on reticulocytes and modest increased iron storage in the spleen. Hepatic hepcidin expression was not affected. Under the condition of reduced heme biosynthesis with reduced iron reutilization and increased storage iron, hepcidin at the lower and higher range of normal showed however a striking role in tissue distribution of iron. Rapid formation of iron-positive inclusion bodies (IB) was observed in circulating reticulocytes, with an ultrastructure of iron-containing polymorphic mitochondrial remnants. IB or mitochondrial iron accumulation was absent in bone marrow erythroblasts. In conclusion, GlyT1 inhibition in rats induced a steady-state microcytic hypochromic regenerative anemia and a species-specific accumulation of uncommitted mitochondrial iron in reticulocytes. Importantly, this glycine restricted anemia provides no feedback signal for increased systemic iron acquisition and the effects reported are pathogenetically distinct from systemic iron-overload anemias and erythropoietic disorders such as acquired sideroblastic anemia.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2016.07.003