CommentaryRole of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease
Graphical abstract
Introduction
Chronic alcohol consumption is a well-known risk factor for liver disease, which represents a major cause of morbidity and mortality worldwide [1]. Progression of alcohol-induced liver disease (ALD) is a multifactorial process that involves a number of genetic, nutritional and environmental factors [2]. Among the mechanisms implicated in the pathogenesis of ALD, oxidative stress has received growing interest [3]. Oxidative stress exists when there is an imbalance between oxidants and antioxidant defenses in favor of the oxidants in the cell. Reactive oxygen species (ROS) are produced by normal cellular metabolism with beneficial effects such as cytotoxicity against bacteria and other pathogens. However, these reactive species also may affect cells of the host organism, by leading to the oxidation of cellular macro-molecules, such as lipids, protein or DNA, inhibiting normal function [4]. For instance, peroxidation of lipids can result in destruction of biological membranes [5], while alterations induced by ROS in different signaling pathways may modulate gene expression, cell metabolism, cell cycle and cell death [5], [6].
Oxidative stress appears to activate the AMP-activated protein kinase (AMPK) signaling system in various cell types, including neuronal, heart, skeletal and vascular smooth muscle, pancreatic and liver cells [7]. AMPK plays a key role in cellular and organism survival during metabolic stress by its ability to maintain metabolic homeostasis. However, it also controls the redox-state and mitochondrial function. Interestingly, AMPK-associated pathways may suppress the cell death induced by oxidative stress [8]. For example, AMPK seems to be required for ROS-triggered autophagy, which promotes cell survival in response to cellular stresses, such as nutrient starvation, hypoxia or ischemia [9].
The first part of this review focuses on the most recent insights concerning the activation of AMPK by oxidative stress. We then describe recent evidence supporting the hypothesis that AMPK signaling pathways play an important role in promoting cell viability under conditions of oxidative stress, such as during alcohol exposure.
Section snippets
Involvement of oxidative stress and AMPK in ALD
Steatosis induced by chronic alcohol consumption can be directly linked to a critical signaling pathway that increases lipogenesis in the liver, i.e., AMPK inhibition [10]. Indeed, AMPK activates fatty acid oxidation and inhibits lipogenesis in rat hepatocytes and in the livers of ethanol-fed mice [11]. The inhibition of AMPK leads to activation of acetyl-CoA carboxylase (ACC), enhancing malonyl CoA levels, which inhibit fatty acid uptake and β-oxidation in mitochondria. However, chronic
AMPK regulates cell death induced by ROS
A decade ago, many studies have shown that AMPK played an important role in the decision between cell survival and death [56]. Early reports showed that pharmacological activation of AMPK protected fibroblast from apoptosis induced by serum withdrawal [57]. AMPK was also shown to play a critical role in protecting the liver from ischemia-reperfusion injury [58]. Based on experiments with AMPK activators and inhibitors, Saberi et al. [59] showed that the upregulation of AMPK promoted hepatocyte
Involvement of AMPK–autophagy axis in ALD
Several direct and indirect arguments suggest that alcohol consumption suppresses liver cell autophagy. First, rats chronically fed with ethanol have a reduced number of autophagic vacuoles in liver cells [107]. Second, chronic ethanol consumption slows down the catabolism of long-lived proteins in the rat liver [108]. Moreover, hepatocytes from patients with alcoholic steatohepatitis contain protein aggregates called Mallory-Denk bodies (MDBs). These Mallory-Denk bodies, the major constituents
Conclusion and future perspectives
Although AMPK has been studied for more than three decades, many questions remain regarding its function, regulation and downstream targets. Depending on the model used, the type of stress applied and the experimental conditions, AMPK may have different roles.
AMPK activation by ROS can promote cell survival by inducing autophagy, mitochondrial biogenesis and expression of genes involved in antioxidant defense. Hence, increased intracellular concentrations of ROS may represent a general
Acknowledgments
This work was supported by grants from Wallonie (Biowin). Julien Verrax is a Belgian Fonds National de la Recherche Scientifique (FNRS) postdoctoral researcher.
References (115)
- et al.
How important is oxidative damage? Lessons from Alzheimer's disease
Free Radic Biol Med
(2000) - et al.
Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species
J Biol Chem
(2004) - et al.
Efficacy of sauchinone as a novel AMPK-activating lignan for preventing iron-induced oxidative stress and liver injury
Free Radic Biol Med
(2009) - et al.
The role of AMP-activated protein kinase in the action of ethanol in the liver
Gastroenterology
(2004) - et al.
Ethanol consumption impairs regulation of fatty acid metabolism by decreasing the activity of AMP-activated protein kinase in rat liver
Biochimie
(2008) - et al.
AICAR potentiates ROS production induced by chronic high glucose: roles of AMPK in pancreatic beta-cell apoptosis
Cell Signal
(2007) - et al.
Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK
J Hepatol
(2011) Sensing of energy and nutrients by AMP-activated protein kinase
Am J Clin Nutr
(2011)- et al.
AMP-activated protein kinase induces actin cytoskeleton reorganization in epithelial cells
Biochem Biophys Res Commun
(2010) - et al.
The regulation of AMP-activated protein kinase by H2O2
Biochem Biophys Res Commun
(2001)
Hydrogen peroxide inhibits mTOR signaling by activation of AMPKalpha leading to apoptosis of neuronal cells
Lab Invest
Increased oxygen radical formation and mitochondrial dysfunction mediate beta cell apoptosis under conditions of AMP-activated protein kinase stimulation
Free Radic Biol Med
LKB1 is the upstream kinase in the AMP-activated protein kinase cascade
Curr Biol
Activation of protein kinase C zeta by peroxynitrite regulates LKB1-dependent AMP-activated protein kinase in cultured endothelial cells
J Biol Chem
ATM deficiency and oxidative stress: a new dimension of defective response to DNA damage
DNA Repair (Amst)
Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells
Cell Metab
Mechanism of action of A-769662, a valuable tool for activation of AMP-activated protein kinase
J Biol Chem
Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase
J Biol Chem
Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems
Free Radic Biol Med
Apoptosis induced by growth factor withdrawal in fibroblasts overproducing fructose 2,6-bisphosphate
FEBS Lett
Adenosine monophosphate-activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat
Hepatology
Involvement of oxygen-regulated protein 150 in AMP-activated protein kinase-mediated alleviation of lipid-induced endoplasmic reticulum stress
J Biol Chem
Mechanism for resveratrol-induced cardioprotection against reperfusion injury involves glycogen synthase kinase 3beta and mitochondrial permeability transition pore
Eur J Pharmacol
AMPK-mediated increase of glycolysis as an adaptive response to oxidative stress in human cells: implication of the cell survival in mitochondrial diseases
Biochim Biophys Acta
Glucose metabolism and Alzheimer's disease
Ageing Res Rev
Sustained activation of AMP-activated protein kinase induces c-Jun N-terminal kinase activation and apoptosis in liver cells
FEBS Lett
5-Aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase
J Biol Chem
Glucose metabolism attenuates p53 and Puma-dependent cell death upon growth factor deprivation
J Biol Chem
The Noxa/Mcl-1 axis regulates susceptibility to apoptosis under glucose limitation in dividing T cells
Immunity
Activation of AMP-activated protein kinase by temozolomide contributes to apoptosis in glioblastoma cells via p53 activation and mTORC1 inhibition
J Biol Chem
Autophagy in liver diseases
J Hepatol
The role of autophagy in mammalian development: cell makeover rather than cell death
Dev Cell
A single protease, Apg4B, is specific for the autophagy-related ubiquitin-like proteins GATE-16, MAP1-LC3, GABARAP, and Apg8L
J Biol Chem
ROS, mitochondria and the regulation of autophagy
Trends Cell Biol
Autophagy in the cardiovascular system
Biochim Biophys Acta
Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy
Cell
AMP-activated protein kinase and the regulation of autophagic proteolysis
J Biol Chem
Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism
Biochem Pharmacol
Alpha-eleostearic acid induces autophagy-dependent cell death through targeting AKT/mTOR and ERK1/2 signal together with the generation of reactive oxygen species
Biochem Biophys Res Commun
Alcoholic liver disease: pathologic, pathogenetic and clinical aspects
Alcohol Clin Exp Res
Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease
Liver Int
Redox signaling and the innate immune system in alcoholic liver disease
Antioxid Redox Signal
Pathological aspects of active oxygens/free radicals
Jpn J Physiol
Roles of reactive oxygen species in hepatocarcinogenesis and drug resistance gene expression in liver cancers
Mol Carcinog
A novel function of poly(ADP-ribose) polymerase-1 in modulation of autophagy and necrosis under oxidative stress
Cell Death Differ
Regulation of hepatic lipin-1 by ethanol: role of AMP-activated protein kinase/sterol regulatory element-binding protein 1 signaling in mice
Hepatology
AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats
Alcohol Clin Exp Res
Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice
Hepatology
Involvement of adiponectin–SIRT1–AMPK signaling in the protective action of rosiglitazone against alcoholic fatty liver in mice
Am J Physiol Gastrointest Liver Physiol
Ethanol administration exacerbates the abnormalities in hepatic lipid oxidation in genetically obese mice
Am J Physiol Gastrointest Liver Physiol
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