Role of AMPK activation in oxidative cell damage: Implications for alcohol-induced liver disease

Abstract

Chronic alcohol consumption is a well-known risk factor for liver disease. Progression of alcohol-induced liver disease (ALD) is a multifactorial process that involves a number of genetic, nutritional and environmental factors. Experimental and clinical studies increasingly show that oxidative damage induced by ethanol contributes in many ways to the pathogenesis of alcohol hepatoxicity. Oxidative stress appears to activate AMP-activated protein kinase (AMPK) signaling system, which has emerged in recent years as a kinase that controls the redox-state and mitochondrial function. This review focuses on the most recent insights concerning the activation of AMPK by reactive oxygen species (ROS), and describes recent evidences 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. We suggest that 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 mechanism for enhancement of AMPK-mediated cellular adaptation, including maintenance of redox homeostasis. On the other hand, AMPK inhibition in the liver by ethanol appears to play a key role in the development of steatosis induced by chronic alcohol consumption. Although more studies are needed to assess the functions of AMPK during oxidative stress, AMPK may be a possible therapeutic target in the particular case of alcohol-induced liver disease.

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.