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


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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    • "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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    ABSTRACT: Chronic ethanol consumption is a strong risk factor for the development of liver disease. Multiple mechanisms are involved in ethanol-mediated liver injury; oxidative stress being pointed has an important factor. However, it should be noted that moderate consumption of red wine has been associated with hepatoprotective effects, mainly due to the antioxidant effect of resveratrol, one of its polyphenolic compounds. In this paper, the potential molecular mechanisms through which the protective effects of resveratrol counteract the oxidative effect of ethanol and the way as this dual effect impacts liver oxidative stress are reviewed. Mechanistic evaluation of modulation of oxidative signaling pathways by ethanol and resveratrol may explain the pathogenesis of various liver diseases and ultimately to disclose possible pharmacological therapies.
    Archives of Toxicology 05/2015; 89(10). DOI:10.1007/s00204-015-1538-1 · 5.98 Impact Factor
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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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    ABSTRACT: Reactive oxygen species, when released in controlled conditions and limited amounts, contribute to cellular proliferation, senescence and survival by acting as signalling intermediates. In the last decades there has been an epidemic diffusion of Non-alcoholic Fatty Liver Disease (NAFLD), that represents the result of the impairment of lipid metabolism, redox unbalance and insulin resistance in the liver. To date, most studies and reviews have been focused on the molecular mechanisms by which fatty liver progresses to steatohepatitis, but the leading processes to the development of hepatic steatosis in NAFLD are not fully understood yet. Several nuclear receptors, such as peroxisome proliferator-activated receptors α/γ/δ (PPAR α/γ/δ), PPARγ co-activators-1α and 1β (PGC-1 α/β), sterol regulatory element-binding proteins (SREBPs), AMP-activated protein kinase (AMPK), liver-X-receptors (LXRs) and farnesoid-X-receptor (FXR), play key roles in the regulation of lipid homeostasis during the pathogenesis of NAFLD. These nuclear receptors may act as redox sensors and may modulate different metabolic pathways in response to specific molecules which act as ligands. It is conceivable that a redox-dependent modulation of lipid metabolism, nuclear receptor-mediated, could cause the development of hepatic steatosis and insulin resistance. Thus, this network may represent a potential therapeutic target for the treatment and prevention of hepatic steatosis and its progression to steatohepatitis. This review summarizes the redox-dependent factors that contribute to the metabolism alterations of fatty liver with a focus on the redox control of nuclear receptors in normal liver as well as in NAFLD.
    Free Radical Biology and Medicine 08/2013; 65. DOI:10.1016/j.freeradbiomed.2013.08.174 · 5.74 Impact Factor
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    • "The pathogenesis of alcoholic liver disease (ALD) is a dynamic process triggered by complex interactions between metabolic intermediates of alcohol, inflammation and immune responses from cellular injury [1], [2]. Since hepatocytes are the primary site of alcohol detoxification, its major toxic metabolic intermediate, acetaldehyde causes direct hepatocyte damage and also forms adducts with proteins and DNA [3], [4]. "
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    ABSTRACT: Chronic ingestion of ethanol increases acetaldehyde and leads to the production of acetaldehyde-derived advanced glycation end-products (AA-AGE). We evaluated the toxicity of AA-AGE on hepatocytes and studied the role of AA-AGE in the pathogenesis of alcoholic liver disease (ALD). Rat hepatocyte cultures were treated with N-ethyllysine (NEL) or AA-AGE and the cell viability was evaluated using MTT assay. Male Wistar rats were fed with liquid diet containing 5% ethanol for 8 weeks following normal diet for another 12 weeks. A group of animals was sacrificed at 4th, 6th, and 8th week and the remaining animals at 12th, 14th, 16th, 18th, and 20th week. The liver sections were stained for AA-AGE and 4-hydroxy-2-nonenal (4-HNE). Liver biopsy obtained from ALD patients was also stained for AA-AGE and 4-HNE. Hepatocyte viability was significantly reduced in cultures treated with AA-AGE compared to NEL treated or control cultures. Severe fatty degeneration was observed during chronic administration of ethanol increasing from 4-8 weeks. The staining of AA-AGE and 4-HNE was correlated with the degree of ALD in both rat and human. In rats, hepatic fatty degeneration was completely disappeared and the staining for both AA-AGE and 4-HNE returned to normal at 12th week of abstinence. Staining for AA-AGE and 4-HNE was completely absent in normal human liver. The data demonstrated that AA-AGE is toxic to hepatocytes, but not NEL. Chronic ethanol ingestion produces AA-AGE and reactive oxygen species that contribute to the pathogenesis of ALD. Abstinence of alcohol results in complete disappearance of both AA-AGE and 4-HNE along with fatty degeneration suggesting that AA-AGE plays a significant role in the pathogenesis of ALD.
    PLoS ONE 07/2013; 8(7):e70034. DOI:10.1371/journal.pone.0070034 · 3.23 Impact Factor
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