Article

Mechanisms and cell signaling in alcoholic liver disease

Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
Biological Chemistry (Impact Factor: 3.27). 11/2010; 391(11):1249-64. DOI: 10.1515/BC.2010.137
Source: PubMed

ABSTRACT

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60%. The poor prognosis of ALD implies that preventing disease progression would be more effective than treating end-stage liver disease. An obvious avenue of prevention would be to remove the damaging agent; however, the infamously high rate of recidivism in alcoholics makes maintaining abstinence a difficult treatment goal to prevent ALD. Indeed, although the progression of ALD is well-characterized, there is no universally accepted therapy available to halt or reverse this process in humans. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of ALD, rational targeted therapy can be developed to treat or prevent ALD. The purpose of this review is to summarize the established and proposed mechanisms by which chronic alcohol abuse damages the liver and to highlight key signaling events known or hypothesized to mediate these effects.

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    • "Hepatocytes have antioxidation enzymes, such as superoxide dismutase (SOD), to mitigate the harm caused by reactive oxygen species and oxidative processes. When this balance is destroyed by alcohol, excessive oxygen free radicals peroxide the biomembrane, causing cell damage and disease [7]. "
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    • "ROS is a collective term used to designate oxygen radicals, such as superoxide anion radical (O 2 ·− ) and hydroxyl radical (HO · ), and also derivatives of oxygen that do not contain unpaired electrons, such as hydrogen peroxide (H 2 O 2 ), singlet oxygen ( 1 O 2 ), and hypochlorous acid (HOCl). These ROS are produced not only by hepatocytes, but also by Kupffer cells (KC), hepatic stellated cells (HSC), endothelial cells, and infiltrating inflammatory leukocytes (Ajakaiye et al. 2011; Beier and McClain 2010). Besides stimulating free radical production, ethanol is also responsible for the impairment of liver antioxidant defences. "
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    • "An example of how oxidative stress may dysregulate redox signaling leading to hepatic steatosis is provided by alcoholic liver disease (ALD) [17]. In fact, the oxidation of ethanol determines a more reduced cellular state and activates the microsomal induction with consequent impaired utilization of oxygen and free radical-induced toxicity [18], which in turn inhibit fatty acid oxidation and promote lipogenesis through the modulation of several NRs [19] [20]. Even though NAFLD is histologically identical to ALD, it is not associated with alcohol consumption and presents a different natural history [21]. "
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