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Knockout of the radical scavenger α1-microglobulin in mice results in defective bikunin synthesis, endoplasmic reticulum stress and increased body weight

Bergwik, Jesper LU ; Kristiansson, Amanda LU ; Welinder, Charlotte LU ; Göransson, Olga LU ; Hansson, Stefan R. LU orcid ; Gram, Magnus LU orcid ; Erlandsson, Lena LU and Åkerström, Bo LU (2021) In Free Radical Biology and Medicine 162.
Abstract

α1-microglobulin (A1M) is a ubiquitous protein with reductase and radical- and heme-binding properties. The protein is mainly expressed in the liver and encoded by the α1-microglobulin-bikunin precursor (AMBP) gene together with the plasma proteinase inhibitor bikunin. The AMBP polypeptide is translated, glycosylated and the C-terminal bikunin part linked via a chondroitin sulfate glycosaminoglycan chain to one or two heavy chains in the endoplasmic reticulum (ER) and Golgi compartments. After proteolytic cleavage, the A1M protein and complexed bikunin parts are secreted separately. The complete physiological role of A1M, and the reason for the co-synthesis with bikunin, are both still unknown. The aim of this work... (More)

α1-microglobulin (A1M) is a ubiquitous protein with reductase and radical- and heme-binding properties. The protein is mainly expressed in the liver and encoded by the α1-microglobulin-bikunin precursor (AMBP) gene together with the plasma proteinase inhibitor bikunin. The AMBP polypeptide is translated, glycosylated and the C-terminal bikunin part linked via a chondroitin sulfate glycosaminoglycan chain to one or two heavy chains in the endoplasmic reticulum (ER) and Golgi compartments. After proteolytic cleavage, the A1M protein and complexed bikunin parts are secreted separately. The complete physiological role of A1M, and the reason for the co-synthesis with bikunin, are both still unknown. The aim of this work was to develop an A1M knockout (A1M−KO) mouse model lacking expression of A1M, but with a preserved bikunin expression, and to study the phenotypic traits in these mice, with a focus on hepatic endoplasmic reticulum (ER) function. The bikunin expression was increased in the A1M−KO mouse livers, while the bikunin levels in plasma were decreased, indicating a defective biosynthesis of bikunin. The A1M−KO livers also showed an increased expression of transducers of the unfolded protein response (UPR), indicating an increased ER-stress in the livers. At twelve months of age, the A1M−KO mice also displayed an increased body weight, and an increased liver weight and lipid accumulation. Moreover, the KO mice showed an increased expression of endogenous antioxidants in the liver, but not in the kidneys. Together, these results suggest a physiological role of A1M as a regulator of the intracellular redox environment and more specifically the ER folding and posttranslational modification processes, particularly in the liver.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
AMBP, Bikunin, ER-Stress, Knockout mouse model, Oxidative stress, α-microglobulin
in
Free Radical Biology and Medicine
volume
162
publisher
Elsevier
external identifiers
  • pmid:32092411
  • scopus:85080926147
ISSN
0891-5849
DOI
10.1016/j.freeradbiomed.2020.02.019
language
English
LU publication?
yes
id
0cc0d5b1-5527-456d-952f-0328cce58bb9
date added to LUP
2020-03-19 15:59:57
date last changed
2021-09-22 04:44:59
@article{0cc0d5b1-5527-456d-952f-0328cce58bb9,
  abstract     = {<p>α<sub>1</sub>-microglobulin (A1M) is a ubiquitous protein with reductase and radical- and heme-binding properties. The protein is mainly expressed in the liver and encoded by the α<sub>1</sub>-microglobulin-bikunin precursor (AMBP) gene together with the plasma proteinase inhibitor bikunin. The AMBP polypeptide is translated, glycosylated and the C-terminal bikunin part linked via a chondroitin sulfate glycosaminoglycan chain to one or two heavy chains in the endoplasmic reticulum (ER) and Golgi compartments. After proteolytic cleavage, the A1M protein and complexed bikunin parts are secreted separately. The complete physiological role of A1M, and the reason for the co-synthesis with bikunin, are both still unknown. The aim of this work was to develop an A1M knockout (A1M−KO) mouse model lacking expression of A1M, but with a preserved bikunin expression, and to study the phenotypic traits in these mice, with a focus on hepatic endoplasmic reticulum (ER) function. The bikunin expression was increased in the A1M−KO mouse livers, while the bikunin levels in plasma were decreased, indicating a defective biosynthesis of bikunin. The A1M−KO livers also showed an increased expression of transducers of the unfolded protein response (UPR), indicating an increased ER-stress in the livers. At twelve months of age, the A1M−KO mice also displayed an increased body weight, and an increased liver weight and lipid accumulation. Moreover, the KO mice showed an increased expression of endogenous antioxidants in the liver, but not in the kidneys. Together, these results suggest a physiological role of A1M as a regulator of the intracellular redox environment and more specifically the ER folding and posttranslational modification processes, particularly in the liver.</p>},
  author       = {Bergwik, Jesper and Kristiansson, Amanda and Welinder, Charlotte and Göransson, Olga and Hansson, Stefan R. and Gram, Magnus and Erlandsson, Lena and Åkerström, Bo},
  issn         = {0891-5849},
  language     = {eng},
  publisher    = {Elsevier},
  series       = {Free Radical Biology and Medicine},
  title        = {Knockout of the radical scavenger α<sub>1</sub>-microglobulin in mice results in defective bikunin synthesis, endoplasmic reticulum stress and increased body weight},
  url          = {http://dx.doi.org/10.1016/j.freeradbiomed.2020.02.019},
  doi          = {10.1016/j.freeradbiomed.2020.02.019},
  volume       = {162},
  year         = {2021},
}