Iron Chaperone Poly rC Binding Protein 1 Protects Mouse Liver From Lipid Peroxidation and Steatosis.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
03 2021
03 2021
Historique:
revised:
06
04
2020
received:
16
12
2019
accepted:
24
04
2020
pubmed:
22
5
2020
medline:
26
8
2021
entrez:
22
5
2020
Statut:
ppublish
Résumé
Iron is essential yet also highly chemically reactive and potentially toxic. The mechanisms that allow cells to use iron safely are not clear; defects in iron management are a causative factor in the cell-death pathway known as ferroptosis. Poly rC binding protein 1 (PCBP1) is a multifunctional protein that serves as a cytosolic iron chaperone, binding and transferring iron to recipient proteins in mammalian cells. Although PCBP1 distributes iron in cells, its role in managing iron in mammalian tissues remains open for study. The liver is highly specialized for iron uptake, utilization, storage, and secretion. Mice lacking PCBP1 in hepatocytes exhibited defects in liver iron homeostasis with low levels of liver iron, reduced activity of iron enzymes, and misregulation of the cell-autonomous iron regulatory system. These mice spontaneously developed liver disease with hepatic steatosis, inflammation, and degeneration. Transcriptome analysis indicated activation of lipid biosynthetic and oxidative-stress response pathways, including the antiferroptotic mediator, glutathione peroxidase type 4. Although PCBP1-deleted livers were iron deficient, dietary iron supplementation did not prevent steatosis; instead, dietary iron restriction and antioxidant therapy with vitamin E prevented liver disease. PCBP1-deleted hepatocytes exhibited increased labile iron and production of reactive oxygen species (ROS), were hypersensitive to iron and pro-oxidants, and accumulated oxidatively damaged lipids because of the reactivity of unchaperoned iron. Unchaperoned iron in PCBP1-deleted mouse hepatocytes leads to production of ROS, resulting in lipid peroxidation (LPO) and steatosis in the absence of iron overload. The iron chaperone activity of PCBP1 is therefore critical for limiting the toxicity of cytosolic iron and may be a key factor in preventing the LPO that triggers the ferroptotic cell-death pathway.
Sections du résumé
BACKGROUND AND AIMS
Iron is essential yet also highly chemically reactive and potentially toxic. The mechanisms that allow cells to use iron safely are not clear; defects in iron management are a causative factor in the cell-death pathway known as ferroptosis. Poly rC binding protein 1 (PCBP1) is a multifunctional protein that serves as a cytosolic iron chaperone, binding and transferring iron to recipient proteins in mammalian cells. Although PCBP1 distributes iron in cells, its role in managing iron in mammalian tissues remains open for study. The liver is highly specialized for iron uptake, utilization, storage, and secretion.
APPROACH AND RESULTS
Mice lacking PCBP1 in hepatocytes exhibited defects in liver iron homeostasis with low levels of liver iron, reduced activity of iron enzymes, and misregulation of the cell-autonomous iron regulatory system. These mice spontaneously developed liver disease with hepatic steatosis, inflammation, and degeneration. Transcriptome analysis indicated activation of lipid biosynthetic and oxidative-stress response pathways, including the antiferroptotic mediator, glutathione peroxidase type 4. Although PCBP1-deleted livers were iron deficient, dietary iron supplementation did not prevent steatosis; instead, dietary iron restriction and antioxidant therapy with vitamin E prevented liver disease. PCBP1-deleted hepatocytes exhibited increased labile iron and production of reactive oxygen species (ROS), were hypersensitive to iron and pro-oxidants, and accumulated oxidatively damaged lipids because of the reactivity of unchaperoned iron.
CONCLUSIONS
Unchaperoned iron in PCBP1-deleted mouse hepatocytes leads to production of ROS, resulting in lipid peroxidation (LPO) and steatosis in the absence of iron overload. The iron chaperone activity of PCBP1 is therefore critical for limiting the toxicity of cytosolic iron and may be a key factor in preventing the LPO that triggers the ferroptotic cell-death pathway.
Identifiants
pubmed: 32438524
doi: 10.1002/hep.31328
pmc: PMC8364740
mid: NIHMS1731957
pii: 01515467-202103000-00026
doi:
Substances chimiques
DNA-Binding Proteins
0
Iron Compounds
0
Metallochaperones
0
Pcbp1 protein, mouse
0
RNA-Binding Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1176-1193Subventions
Organisme : CSR NIH HHS
ID : HL114453-06
Pays : United States
Organisme : NIH HHS
ID : S10 OD016232
Pays : United States
Organisme : Intramural NIH HHS
ID : Z01 DK054512
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI068021
Pays : United States
Organisme : NIH HHS
ID : S10 OD018210
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM066698
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL114453
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54DK11085804
Pays : United States
Organisme : NIH HHS
ID : S10 OD021505
Pays : United States
Organisme : NIGMS NIH HHS
ID : GM79645
Pays : United States
Organisme : CSR NIH HHS
ID : U19AI068021
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK110858
Pays : United States
Informations de copyright
© 2020 by the American Association for the Study of Liver Diseases.
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