| Chronic Ethanol Consumption in Mice Alters Hepatocyte Lipid Droplet Properties. | |
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MedLine Citation:
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PMID: 21535024 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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Background: Hepatosteatosis is a common pathological feature of impaired hepatic metabolism following chronic alcohol consumption. Although often benign and reversible, it is widely believed that steatosis is a risk factor for development of advanced liver pathologies, including steatohepatitis and fibrosis. The hepatocyte alterations accompanying the initiation of steatosis are not yet clearly defined. Methods: Induction of hepatosteatosis by chronic ethanol consumption was investigated using the Lieber-DeCarli (LD) high fat diet model. Effects were assessed by immunohistochemistry and blood and tissue enzymatic assays. Cell culture models were employed for mechanistic studies. Results: Pair feeding mice ethanol (LD-Et) or isocaloric control (LD-Co) diets for 6 weeks progressively increased hepatocyte triglyceride accumulation in morphological, biochemical, and zonally distinct cytoplasmic lipid droplets (CLD). The LD-Et diet induced zone 2-specific triglyceride accumulation in large CLD coated with perilipin, adipophilin (ADPH), and TIP47. In LD-Co-fed mice, CLD were significantly smaller than those in LD-Et-fed mice and lacked perilipin. A direct role of perilipin in formation of large CLD was further suggested by cell culture studies showing that perilipin-coated CLD were significantly larger than those coated with ADPH or TIP47. LD-Co- and LD-Et-fed animals also differed in hepatic metabolic stress responses. In LD-Et but not LD-Co-fed mice, inductions were observed in the following: microsomal ethanol-oxidizing system [cytochrome P-4502E1 (CYP2E1)], hypoxia response pathway (hypoxia-inducible factor 1 alpha, HIF1α), endoplasmic reticulum stress pathway (calreticulin), and synthesis of lipid peroxidation products [4-hydroxynonenal (4-HNE)]. CYP2E1 and HIF1 α immunostaining localized to zone 3 and did not correlate with accumulation of large CLD. In contrast, calreticulin and 4-HNE immunostaining closely correlated with large CLD accumulation. Importantly, 4-HNE staining significantly colocalized with ADPH and perilipin on the CLD surface. Conclusions: These data suggest that ethanol contributes to macrosteatosis by both altering CLD protein composition and inducing lipid peroxide adduction of CLD-associated proteins. |
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Authors:
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David J Orlicky; James R Roede; Elise Bales; Carrie Greenwood; Andrew Greenberg; Dennis Petersen; James L McManaman |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-4-27 |
Journal Detail:
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Title: Alcoholism, clinical and experimental research Volume: - ISSN: 1530-0277 ISO Abbreviation: - Publication Date: 2011 Apr |
Date Detail:
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Created Date: 2011-5-3 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 Pathology (DJO), University of Colorado Anschutz Medical Campus, Aurora, Colorado; Pharmaceutical Sciences (JRR, DP), University of Colorado Anschutz Medical Campus, Aurora, Colorado; Obstetrics and Gynecology (EB, CG, JLM), University of Colorado Anschutz Medical Campus, Aurora, Colorado; and Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging (AG), Tufts University, Boston, Massachusetts. |
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