Vitamin E Induces Liver Iron Depletion and Alters Iron Regulation in Mice.
bone morphogenetic protein
ferroportin
ferroptosis
hepcidin
iron homeostasis
Journal
The Journal of nutrition
ISSN: 1541-6100
Titre abrégé: J Nutr
Pays: United States
ID NLM: 0404243
Informations de publication
Date de publication:
07 2023
07 2023
Historique:
received:
08
03
2023
revised:
14
04
2023
accepted:
27
04
2023
pmc-release:
29
04
2024
medline:
10
7
2023
pubmed:
2
5
2023
entrez:
1
5
2023
Statut:
ppublish
Résumé
Vitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice lacking a critical liver iron-trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements. We aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver. C57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet. The Vit E-fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2-related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin, an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05). Oral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative effects of vit E.
Sections du résumé
BACKGROUND
Vitamin E (vit E) is an essential nutrient that functions as a lipophilic antioxidant and is used clinically to treat nonalcoholic fatty liver disease, where it suppresses oxidative damage and impedes the progression of steatosis and fibrosis. Mice lacking a critical liver iron-trafficking protein also manifest steatosis because of iron-mediated oxidative damage and are protected from liver disease by oral vit E supplements.
OBJECTIVES
We aimed to examine the role of dietary vit E supplementation in modulating iron-sensing regulatory systems and nonheme iron levels in mouse liver.
METHODS
C57Bl/6 male mice, aged 6 wk, were fed purified diets containing normal amounts of iron and either control (45 mg/kg) or elevated (450 mg/kg) levels of 2R-α-tocopherol (vit E) for 18 d. Mouse plasma and liver were analyzed for nonheme iron, levels and activity of iron homeostatic proteins, and markers of oxidative stress. We compared means ± SD for iron and oxidative stress parameters between mice fed the control diet and those fed the vit E diet.
RESULTS
The Vit E-fed mice exhibited lower levels of liver nonheme iron (38% reduction, P < 0.0001) and ferritin (74% reduction, P < 0.01) than control-fed mice. The levels of liver mRNA for transferrin receptor 1 and divalent metal transporter 1 were reduced to 42% and 57% of the control, respectively. The mRNA levels for targets of nuclear factor erythroid 2-related factor (Nrf2), a major regulator of the oxidative stress response and iron-responsive genes, were also suppressed in vit E livers. Hepcidin, an iron regulatory hormone, levels were lower in the plasma (P < 0.05), and ferroportin (FPN), the iron exporter regulated by hepcidin, was expressed at higher levels in the liver (P < 0.05).
CONCLUSIONS
Oral vit E supplementation in mice can lead to depletion of liver iron stores by suppressing the iron- and redox-sensing transcription factor Nrf2, leading to enhanced iron efflux through liver FPN. Iron depletion may indirectly enhance the antioxidative effects of vit E.
Identifiants
pubmed: 37127137
pii: S0022-3166(23)37589-8
doi: 10.1016/j.tjnut.2023.04.018
pmc: PMC10375508
pii:
doi:
Substances chimiques
Iron
E1UOL152H7
Vitamin E
1406-18-4
Hepcidins
0
NF-E2-Related Factor 2
0
Antioxidants
0
RNA, Messenger
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1866-1876Informations de copyright
Published by Elsevier Inc.
Références
Cochrane Database Syst Rev. 2017 Apr 18;4:CD002854
pubmed: 28418065
PLoS One. 2013;8(4):e60534
pubmed: 23565256
PLoS Pathog. 2015 Aug 20;11(8):e1004998
pubmed: 26291319
Blood Cells Mol Dis. 2018 Mar;69:75-81
pubmed: 29032941
Semin Hematol. 2021 Jul;58(3):161-174
pubmed: 34389108
Int J Mol Sci. 2021 Jun 17;22(12):
pubmed: 34204327
Antioxidants (Basel). 2022 Jan 26;11(2):
pubmed: 35204118
Haematologica. 2010 Aug;95(8):1261-8
pubmed: 20179090
Antioxidants (Basel). 2021 Jan 26;10(2):
pubmed: 33530432
Curr Gastroenterol Rep. 2012 Feb;14(1):8-16
pubmed: 22124850
Bioresour Technol. 2008 Dec;99(18):8705-9
pubmed: 18550368
J Lipid Res. 2020 May;61(5):707-721
pubmed: 32086244
N Engl J Med. 2005 Jun 9;352(23):2379-88
pubmed: 15829527
Mol Cell Biol. 2006 Mar;26(6):2373-86
pubmed: 16508012
J Biochem Mol Toxicol. 2005;19(5):298-303
pubmed: 16292753
Free Radic Biol Med. 2021 Nov 1;175:18-27
pubmed: 34455040
Cochrane Database Syst Rev. 2017 Jul 31;7:CD000254
pubmed: 28756618
Haematologica. 2020 Feb 13;105(10):e493
pubmed: 33054090
Hepatology. 2021 Mar;73(3):1176-1193
pubmed: 32438524
Nat Metab. 2019 May;1(5):519-531
pubmed: 31276102
Blood. 2016 Jun 9;127(23):2809-13
pubmed: 27044621
Am J Hematol. 2017 Nov;92(11):1204-1213
pubmed: 28815688
Am Fam Physician. 1997 Jan;55(1):197-201
pubmed: 9012278
Nature. 2014 May 1;509(7498):105-9
pubmed: 24695223
Anal Biochem. 2009 Jun 15;389(2):124-9
pubmed: 19341701
Proc Natl Acad Sci U S A. 1988 Jul;85(14):5166-70
pubmed: 2839833
Br J Nutr. 2000 Sep;84(3):261-7
pubmed: 10967604
EMBO J. 2004 Jan 28;23(2):386-95
pubmed: 14726953
Metab Syndr Relat Disord. 2011 Aug;9(4):287-90
pubmed: 21417913
Am J Clin Nutr. 2007 Jan;85(1):293S-299S
pubmed: 17209213
Nat Cell Biol. 2014 Nov;16(11):1069-79
pubmed: 25327288
J Lipid Res. 2018 Sep;59(9):1597-1609
pubmed: 30084831
Molecules. 2019 Apr 07;24(7):
pubmed: 30959950
Nutrients. 2017 Sep 11;9(9):
pubmed: 28892009
Annu Rev Nutr. 2021 Oct 11;41:105-131
pubmed: 34115520
JAMA. 2013 May 15;309(19):2005-15
pubmed: 23644932
Antioxid Redox Signal. 2018 Dec 10;29(17):1727-1745
pubmed: 28899199
Am J Clin Nutr. 2019 Nov 1;110(5):1148-1167
pubmed: 31495886
Br J Haematol. 2021 Jun;193(5):882-893
pubmed: 33316086
JAMA. 2005 Jul 6;294(1):56-65
pubmed: 15998891
Curr Top Membr. 2012;70:169-214
pubmed: 23177986
Front Pharmacol. 2022 Apr 12;13:869794
pubmed: 35496274
N Engl J Med. 2000 Jun 22;342(25):1917-8
pubmed: 10877639
Cell Death Dis. 2019 Jun 18;10(6):449
pubmed: 31209199
JCI Insight. 2020 Jan 16;5(1):
pubmed: 31821172
Liver Int. 2018 Jan;38(1):164-173
pubmed: 28679028
N Engl J Med. 2010 May 6;362(18):1675-85
pubmed: 20427778
World J Gastroenterol. 2016 Jun 7;22(21):5096-103
pubmed: 27275102
J Clin Invest. 2017 May 1;127(5):1786-1797
pubmed: 28375153
JAMA. 2005 Mar 16;293(11):1338-47
pubmed: 15769967
J Biol Chem. 2017 Aug 4;292(31):12744-12753
pubmed: 28615439
J Lipid Res. 2015 Nov;56(11):2217-25
pubmed: 26351363
N Engl J Med. 1994 Apr 14;330(15):1029-35
pubmed: 8127329
Hepatology. 2020 Feb;71(2):495-509
pubmed: 30506586
Blood. 2011 Jul 21;118(3):747-56
pubmed: 21622652
Mol Med. 2018 Mar 15;24(1):5
pubmed: 30134796
Redox Biol. 2020 Oct;37:101710
pubmed: 32920226
JAMA. 2008 Nov 12;300(18):2123-33
pubmed: 18997197
Elife. 2015 Oct 05;4:
pubmed: 26436293
J Nutr. 2001 Feb;131(2):374S-7S
pubmed: 11160564
Blood. 2008 Nov 15;112(10):4292-7
pubmed: 18689548
JAMA. 2011 Oct 12;306(14):1549-56
pubmed: 21990298
IUBMB Life. 2019 Apr;71(4):411-415
pubmed: 30550633
Neuroscience. 2014 Feb 28;260:120-9
pubmed: 24342566
Free Radic Biol Med. 2021 Jan;162:592-602
pubmed: 33248265
Bone. 2020 Sep;138:115495
pubmed: 32585319