Abstract
Iron-mediated induction of bone morphogenetic protein (BMP)6 expression by liver endothelial cells is essential for iron homeostasis regulation. We used multiple dietary and genetic mouse cohorts to demonstrate a minor functional role for the metal-ion transporter ZIP8 in regulating BMP6 expression under high-iron conditions.
Subjects:
Red Cells, Iron, and Erythropoiesis
References
1.
Nemeth
E
, Tuttle
MS
, Powelson
J
, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization
. Science
. 2004
;306
(5704
):2090
-2093
.2.
Ganz
T
, Olbina
G
, Girelli
D
, Nemeth
E
, Westerman
M
. Immunoassay for human serum hepcidin
. Blood
. 2008
;112
(10
):4292
-4297
.3.
Fisher
AL
, Nemeth
E
. Iron homeostasis during pregnancy
. Am J Clin Nutr
. 2017
;106
(suppl 6
):1567s
-1574s
.4.
Nemeth
E
, Rivera
S
, Gabayan
V
, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin
. J Clin Invest
. 2004
;113
(9
):1271
-1276
.5.
Camaschella
C
, Nai
A
, Silvestri
L
. Iron metabolism and iron disorders revisited in the hepcidin era
. Haematologica
. 2020
;105
(2
):260
-272
.6.
Fisher
AL
, Babitt
JL
. Coordination of iron homeostasis by bone morphogenetic proteins: current understanding and unanswered questions
. Dev Dyn
. 2022
;251
(1
):26
-46
.7.
Canali
S
, Zumbrennen-Bullough
KB
, Core
AB
, et al. Endothelial cells produce bone morphogenetic protein 6 required for iron homeostasis in mice
. Blood
. 2017
;129
(4
):405
-414
.8.
Canali
S
, Wang
CY
, Zumbrennen-Bullough
KB
, Bayer
A
, Babitt
JL
. Bone morphogenetic protein 2 controls iron homeostasis in mice independent of Bmp6
. Am J Hematol
. 2017
;92
(11
):1204
-1213
.9.
Koch
P-S
, Olsavszky
V
, Ulbrich
F
, et al. Angiocrine Bmp2 signaling in murine liver controls normal iron homeostasis
. Blood
. 2017
;129
(4
):415
-419
.10.
Kautz
L
, Besson-Fournier
C
, Meynard
D
, Latour
C
, Roth
MP
, Coppin
H
. Iron overload induces BMP6 expression in the liver but not in the duodenum
. Haematologica
. 2011
;96
(2
):199
-203
.11.
Wang
CY
, Canali
S
, Bayer
A
, Dev
S
, Agarwal
A
, Babitt
JL
. Iron, erythropoietin, and inflammation regulate hepcidin in Bmp2-deficient mice, but serum iron fails to induce hepcidin in Bmp6-deficient mice
. Am J Hematol
. 2019
;94
(2
):240
-248
.12.
Corradini
E
, Meynard
D
, Wu
Q
, et al. Serum and liver iron differently regulate the bone morphogenetic protein 6 (BMP6)-SMAD signaling pathway in mice
. Hepatology
. 2011
;54
(1
):273
-284
.13.
Xiao
X
, Dev
S
, Canali
S
, et al. Endothelial bone morphogenetic protein 2 (Bmp2) knockout exacerbates hemochromatosis in homeostatic iron regulator (Hfe) knockout mice but not Bmp6 knockout mice
. Hepatology
. 2020
;72
(2
):642
-655
.14.
Lim
PJ
, Duarte
TL
, Arezes
J
, et al. Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin
. Nat Metab
. 2019
;1
(5
):519
-531
.15.
Fisher
AL
, Wang
C-Y
, Xu
Y
, et al. Quantitative proteomics and RNA-sequencing of mouse liver endothelial cells identify novel regulators of BMP6 by iron
. iScience
. 2023
;26
(12
):108555
.16.
Fisher
AL
, Wang
C-y
, Xu
Y
, et al. Functional role of endothelial transferrin receptor 1 in iron sensing and homeostasis
. Am J Hematol
. 2022
;97
(12
):1548
-1559
.17.
Charlebois
E
, Fillebeen
C
, Presley
J
, et al. Liver sinusoidal endothelial cells induce BMP6 expression in response to non–transferrin-bound iron
. Blood
. 2023
;141
(3
):271
-284
.18.
Géraud
C
, Schledzewski
K
, Demory
A
, et al. Liver sinusoidal endothelium: a microenvironment-dependent differentiation program in rat including the novel junctional protein liver endothelial differentiation-associated protein-1
. Hepatology
. 2010
;52
(1
):313
-326
.19.
Tabula Muris Consortium, Overall coordination, Logistical coordination
, et al. Single-cell transcriptomics of 20 mouse organs creates a Tabula Muris
. Nature
. 2018
;562
(7727
):367
-372
.20.
Knutson
MD
. Non–transferrin-bound iron takes the driver’s seat
. Blood
. 2023
;141
(3
):214
-216
.21.
Géraud
C
, Koch
P-S
, Zierow
J
, et al. GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis
. J Clin Invest
. 2017
;127
(3
):1099
-1114
.22.
Torrance
JD
, Bothwell
TH
. A simple technique for measuring storage iron concentrations in formalinised liver samples
. S Afr J Med Sci
. 1968
;33
(1
):9
-11
.23.
Wang
C-Y
, Jenkitkasemwong
S
, Duarte
S
, et al. ZIP8 is an iron and zinc transporter whose cell-surface expression is up-regulated by cellular iron loading
. J Biol Chem
. 2012
;287
(41
):34032
-34043
.24.
Jenkitkasemwong
S
, Wang
CY
, Coffey
R
, et al. SLC39A14 is required for the development of hepatocellular iron overload in murine models of hereditary hemochromatosis
. Cell Metab
. 2015
;22
(1
):138
-150
.© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.
2024
You do not currently have access to this content.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal