| Limited Therapeutic Effect of N-Acetylcysteine on Hepatic Insulin Resistance in an Experimental Model of Alcohol-Induced Steatohepatitis. | |
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MedLine Citation:
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PMID: 21790669 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background: Alcohol-related steatohepatitis is associated with increased oxidative stress, DNA damage, lipotoxicity, and insulin resistance in liver. As inflammation and oxidative stress can promote insulin resistance, effective treatment with antioxidants, for example, N-acetylcysteine (NAC), may restore ethanol-impaired insulin signaling in the liver. Methods: Adult male Sprague-Dawley rats were fed for 130 days with liquid diets containing 0 or 37% ethanol by caloric content, and simultaneously treated with vehicle or NAC. Chow-fed controls were studied in parallel. Liver tissues were used for histopathology, cytokine activation, and insulin/IGF-1 signaling assays. Results: We observed significant positive trends of increasing severity of steatohepatitis (p = 0.016) with accumulation of neutral lipid (p = 0.0002) and triglycerides (p = 0.0004) from chow to control, to the ethanol diet, irrespective of NAC treatment. In ethanol-fed rats, NAC reduced inflammation, converted the steatosis from a predominantly microvesicular to a mainly macrovesicular histological pattern, reduced pro-inflammatory cytokine gene expression, ceramide load, and acid sphingomyelinase activity, and increased expression of IGF-1 receptor and IGF-2 in liver. However, NAC did not abrogate ethanol-mediated impairments in signaling through insulin/IGF-1 receptors, IRS-1, Akt, GSK-3β, or p70S6K, nor did it significantly reduce pro-ceramide or GM3 ganglioside gene expression in liver. Conclusions: Antioxidant treatments reduce the severity of chronic alcohol-related steatohepatitis, possibly because of the decreased expression of inflammatory mediators and ceramide accumulation, but they do not restore insulin/IGF-1 signaling in liver, most likely due to persistent elevation of GM3 synthase expression. Effective treatment of alcohol-related steatohepatitis most likely requires dual targeting of oxidative stress and insulin/IGF resistance. |
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Authors:
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Mashiko Setshedi; Lisa Longato; Dennis R Petersen; Martin Ronis; William C Chen; Jack R Wands; Suzanne M de la Monte |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-7-25 |
Journal Detail:
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Title: Alcoholism, clinical and experimental research Volume: - ISSN: 1530-0277 ISO Abbreviation: - Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-7-27 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7707242 Medline TA: Alcohol Clin Exp Res Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 by the Research Society on Alcoholism. |
Affiliation:
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From the Department of Medicine (MS, WCC, JRW, SMdlM), the Pathobiology Graduate Program (LL, JRW, SMdlM), and the Department of Pathology (SMdlM), Rhode Island Hospital, and the Alpert Medical School of Brown University (SMdlM), Brown University, Providence, Rhode Island; Department of Internal Medicine (MS), University of Cape Town, Cape Town, South Africa; Department of Pharmaceutical Sciences (DRP), University of Colorado Health Sciences Center, Denver, Colorado; and Departments of Pharmacology & Toxicology (MR), Arkansas Children's Nutrition Center and the University of Arkansas for Medical Sciences, Little Rock, Arkansas. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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