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: 2.69). 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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    • "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 · 5.71 Impact Factor
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    • "providing mechanistic information on binge EtOH effect relevant to ALD. It is increasingly being recognized that the cellular effects of EtOH are due to modulation of immunological , metabolic, signaling, and epigenetic pathways (Beier and McClain, 2010; Gao et al., 2011; Shukla et al., 2008). Binge has profound effect on these mechanisms (Fig. 1). "
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    ABSTRACT: Binge consumption of alcohol is an alarming global health problem. Binge (acute) ethanol (EtOH) is implicated in the pathophysiology of alcoholic liver disease (ALD). New studies from experimental animals and from humans indicate that binge EtOH has profound effects on immunological, signaling, and epigenetic parameters of the liver. This is in addition to the known metabolic effects of acute EtOH. Binge EtOH alters the levels of several cellular components and dramatically amplifies liver injury in chronically EtOH exposed liver. These studies highlight the importance of molecular investigations into binge effects of EtOH for a better understanding of ALD and also to develop therapeutic strategies to control it. This review summarizes these recent developments.
    Alcoholism Clinical and Experimental Research 01/2013; 37(4). DOI:10.1111/acer.12011 · 3.31 Impact Factor
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    • "A major problem in the treatment for alcoholic liver disease remains the adherence of patients to abstinence from alcohol. Many studies have been carried out to determine the effectiveness of therapy in reducing the progression of liver injury in alcoholics (Beier and McClain, 2010). The experimental model used in the present study has striking similarities to the clinical setting in which alcoholic liver disease occurs. "
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    ABSTRACT: BACKGROUND: Thromboxane levels are increased in rats fed ethanol (EtOH), whereas thromboxane inhibitors reduce alcoholic liver injury. The aim of this study is to determine whether thromboxane inhibitors could attenuate the already established alcoholic liver injury. METHODS: Rats were fed EtOH and liquid diet for 6 weeks by intragastric infusion to induce liver injury after which EtOH was continued for 2 more weeks, and the rats were treated with either a thromboxane synthase inhibitor (TXSI) or a thromboxane receptor antagonist (TXRA). Liver pathology, lipid peroxidation, nuclear factor-kappa-B (NF-κB) activity, tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2), and transforming growth factor-beta1 (TGF-β(1) ) were evaluated. RESULTS: Administration of fish oil and EtOH caused fatty liver, necrosis, inflammation and fibrosis accompanied by increased in lipid peroxidation, NF-κB activity, and expression of TNF-α, COX-2, and TGF-β(1) . Treatment with the thromboxane inhibitors ameliorated a certain level of the pathological and biochemical abnormalities. In particular, TXSI in addition to reducing necrosis, inflammation and fibrosis also decrease the severity of fatty liver. CONCLUSIONS: Thromboxane inhibitors attenuated the alcoholic liver injury, inflammation and fibrotic changes despite continued EtOH administration. Inhibition of the production of thromboxane by thromboxane inhibitor and receptor antagonists may be a useful treatment strategy in clinical alcoholic liver disease.
    Alcoholism Clinical and Experimental Research 06/2012; 37(1). DOI:10.1111/j.1530-0277.2012.01838.x · 3.31 Impact Factor
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