title: Activated AMPK boosts the Nrf2/HO-1 signaling axis--A role for the unfolded protein response.
abstract: 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.
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Kristin
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Baldinger
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mayerhofer
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Atanas G
authors.initials: AG
authors.lastname: Atanasov
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.
authors.forename: Verena M
authors.initials: VM
authors.lastname: Dirsch
authors.affiliation: Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Electronic address: elke.heiss@univie.ac.at.
authors.forename: Elke H
authors.initials: EH
authors.lastname: Heiss
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D011427:Propiophenones / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020239:Receptor Cross-Talk / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D005419:Flavonoids; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011427:Propiophenones; D017382:Reactive Oxygen Species; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D055372:AMP-Activated Protein Kinases; C104536:xanthohumol
keywords: AMPK; ER stress; HO-1; LKB1; MEF; Nrf2; PERK; Xanthohumol
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