Activated AMPK boosts the Nrf2/HO-1 signaling axis—A role for the unfolded protein response

Autor: Zimmermann, Kristin, Baldinger, Johannes, Mayerhofer, Barbara, Atanasov, Atanas G., Dirsch, Verena M., Heiss, Elke H.
Jazyk: angličtina
Rok vydání: 2015
Předmět:
WT
wild type
AMPK
ACC
acetyl-CoA carboxylase
HO-1
heme oxygenase 1
DMSO
dimethyl sulfoxide
AMP-Activated Protein Kinases
Biochemistry
environment and public health
Mice
UPR
unfolded protein response
OCR
oxygen consumption rate
MEF
Propiophenones
AMPK
AMP-activated kinase
GSSG
oxidized glutathione
Xanthohumol
respiratory system
Maf
small musculoaponeurotic fibrosarcoma
Flow Cytometry
Mitochondria
ER stress
TAK
transforming growth factor β-activated kinase
Oxidation-Reduction
Signal Transduction
PERK
GSH
glutathione (reduced)
LKB1
NF-E2-Related Factor 2
Blotting
Western
HO-1
ARE
antioxidant response element
mTOR
mammalian target of rapamycin
βTrcP1
β-transducin-repeat containing protein 1
Real-Time Polymerase Chain Reaction
CHO
Chinese hamster ovary
Article
Nrf2
ER
endoplasmic reticulum
Keap1
Kelch-like ECH-associated protein
LKB1
liver kinase B1
ROS
reactive oxygen species
GSK3β
glycogen synthase kinase 3β
Physiology (medical)
Animals
MEF
mouse embryonic fibroblasts
Flavonoids
Hrd1
synoviolin/Hrd1 (HMG-CoA reductase degradation)-ubiquitin ligase
PERK
protein kinase RNA-like endoplasmic reticulum kinase
Nrf2
nuclear factor E2-related factor 2
Membrane Proteins
CaMKK
calcium calmodulin-dependent kinase kinase
Receptor Cross-Talk
NADPH
nicotinamide adenine dinucleotide phosphate
Fibroblasts
Oxidative Stress
DCF
dichlorofluorescein
Unfolded Protein Response
FCS
fetal calf serum
XN/Xn
xanthohumol
Reactive Oxygen Species
Heme Oxygenase-1
Zdroj: Free Radical Biology & Medicine
ISSN: 1873-4596
0891-5849
Popis: In light of the emerging interplay between redox and metabolic signaling pathways we investigated the potential cross talk between nuclear factor E2-related factor 2 (Nrf2) and AMP-activated kinase (AMPK), central regulators of the cellular redox and energy balance, respectively. Making use of xanthohumol (XN) as an activator of both the AMPK and the Nrf2 signaling pathway we show that AMPK exerts a positive influence on Nrf2/heme oxygenase (HO)-1 signaling in mouse embryonic fibroblasts. Genetic ablation and pharmacological inhibition of AMPK blunts Nrf2-dependent HO-1 expression by XN already at the mRNA level. XN leads to AMPK activation via interference with mitochondrial function and activation of liver kinase B1 as upstream AMPK kinase. The subsequent AMPK-mediated enhancement of the Nrf2/HO-1 response does not depend on inhibition of the mammalian target of rapamycin, inhibition of glycogen synthase kinase 3β, or altered abundance of Nrf2 (total and nuclear). However, reduced endoplasmic reticulum stress was identified and elaborated as a step in the AMPK-augmented Nrf2/HO-1 response. Overall, we shed more light on the hitherto incompletely understood cross talk between the LKB1/AMPK and the Nrf2/HO-1 axis revealing for the first time involvement of the unfolded protein response as an additional player and suggesting tight cooperation between signaling pathways controlling cellular redox, energy, or protein homeostasis.
Graphical abstract
Highlights • Activated AMPK boosts the Nrf2/HO‐1 signaling axis in xanthohumol‐treated cells. • Xanthohumol leads to AMPK activation in an LKB1‐dependent manner. • The AMPK boost hits on a step prior to or at transcription of HO‐1 mRNA. • Inhibition of GSK3β or mTOR is not involved in the observed AMPK boost. • Higher ER stress accounts for the lower Nrf2/HO1 response in AMPK‐deficient cells.
Databáze: OpenAIRE
Externí odkaz: