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.

Long Non-Coding RNA MALAT1 Protects Human Osteoblasts from Dexamethasone-Induced Injury via Activation of PPM1E-AMPK Signaling

“…AMPK is shown to directly phosphorylate Nrf2 (at Ser-550) to increase Nrf2 nuclear translocation and activation [29]. Zimmermann et al previously reported a signaling crosstalk between AMPK and Nrf2 [28]. Compound 991 and PF-06409577, two well-known AMPK activators, have also been shown to activate Nrf2 signaling [30,45].…”

“…Activated AMPK can increase NADPH content and activity to attenuate oxidative stress [49,51]. AMPK can also induce activation of Nrf2 signaling [28][29][30], which is a key cellular defense mechanism against oxidative stress [52][53][54]. In OB-6 cells, transfection with LV-MALAT1 significantly enhanced the mRNA and protein expression of several key Nrf2-dependent enzymes, including HO1, NOQ1, and GCLC ( Fig.…”

“…Activated AMPK is shown to promote cell survival under stress conditions [26]. AMPK can attenuate oxidative stress via activation of nicotinamide adenine dinucleotide phosphate (NADPH) [27] and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling [28][29][30]. Recent studies have implied that AMPK activation can efficiently protect human osteoblasts from Dex-induced injuries [4,5,30,31].…”

Nuclear Factor–Erythroid-2–Related Factor 2 in Aging and Lung Fibrosis

“…91 In the unfolded protein response, activation of AMPK up-regulates Nrf2/HO-1 signaling in mouse embryonic fibroblasts. 94 Defining the precise role of AMPK in age-related regulation of Nrf2 signaling has the potential for clinical translation. Sumoylation has been reported to be involved in regulating Nrf2 signaling.…”

The apolipoprotein A‐I mimetic peptide, D‐4F, restrains neointimal formation through heme oxygenase‐1 up‐regulation

“…AMP‐activated protein kinase (AMPK) acts as a central regulator in the cellular redox 26. Therefore, the roles of Akt and AMPK in the expression of HO‐1 were evaluated.…”