| Chronic alcohol consumption disrupted cholesterol homeostasis in rats: down-regulation of low-density lipoprotein receptor and enhancement of cholesterol biosynthesis pathway in the liver. | |
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MedLine Citation:
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PMID: 20028367 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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BACKGROUND: Chronic alcohol consumption causes alcoholic liver disease, which is associated, or initiated, with dysregulated lipid metabolism. Very recent evidence suggested that dysregulated cholesterol metabolism plays an important role in the pathogenesis of alcoholic fatty liver diseases, however, the effects of chronic alcohol exposure on cholesterol homeostasis have not been well studied and underlying mechanisms behind are still elusive. METHODS: Male Sprague-Dawley rats weighing 250 +/- 5.5 g (mean +/- SEM) divided into 2 groups (8 rats per group) and pair-fed with liquid diets containing (in percent of energy intake) 18% protein, 35% fat, 12% carbohydrate, and 35% either ethanol (ethanol diet) or an isocaloric maltose-dextrin mixture (control diet), according to Lieber and De Carli, for 4 weeks. RESULTS: Long-term excessive alcohol feeding to rats caused fatty liver and liver injury, which was associated with disrupted cholesterol homeostasis, characterized by increased hepatic cholesterol levels and hypercholesterolemia. Hepatic cholesterol increases were concomitant with constantly activated sterol regulatory element-binding protein-2 (SREBP-2) in the liver and increased expression of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, a rate-limiting enzyme for cholesterol de novo synthesis, indicating enhanced cholesterol biosynthesis. Alcohol-induced hypercholesterolemia was accompanied by decreased LDL receptor (LDLr) levels in the liver. Further investigations revealed that chronic alcohol exposure increased hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) contents to down-regulate LDLr via a post-translational mechanism. Moreover, alcohol feeding suppressed extracellular signal-regulated kinase (ERK) activation in the liver. In vitro studies showed that inhibition of ERK activation was associated with decreased LDLr expression in HepG2 cells. CONCLUSIONS: Our study provides the first evidence that both increased PCSK9 expression and suppressed ERK activation in the liver contributes to alcohol-induced hypercholesterolemia in rats. |
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Authors:
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Zhigang Wang; Tong Yao; Zhenyuan Song |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2009-12-18 |
Journal Detail:
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Title: Alcoholism, clinical and experimental research Volume: 34 ISSN: 1530-0277 ISO Abbreviation: Alcohol. Clin. Exp. Res. Publication Date: 2010 Mar |
Date Detail:
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Created Date: 2010-04-21 Completed Date: 2010-08-03 Revised Date: 2012-01-19 |
Medline Journal Info:
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Nlm Unique ID: 7707242 Medline TA: Alcohol Clin Exp Res Country: England |
Other Details:
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Languages: eng Pagination: 471-8 Citation Subset: IM |
Affiliation:
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Department of Human Nutrition, University of Illinois at Chicago, Illinois 60612, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Alcohol Drinking
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metabolism Animals Central Nervous System Depressants / administration & dosage, adverse effects*, metabolism Cholesterol / biosynthesis* Down-Regulation Ethanol / administration & dosage, adverse effects*, metabolism Extracellular Signal-Regulated MAP Kinases / metabolism Homeostasis Hypercholesterolemia / chemically induced Lipid Metabolism / drug effects Liver / drug effects*, metabolism Liver Diseases, Alcoholic / etiology, metabolism* Male Rats Rats, Sprague-Dawley Receptors, LDL / metabolism Serine Endopeptidases / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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K01 AA015344/AA/NIAAA NIH HHS; K01 AA015344-05/AA/NIAAA NIH HHS; R01 AA017442/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Central Nervous System Depressants; 0/Receptors, LDL; 57-88-5/Cholesterol; 64-17-5/Ethanol; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases; EC 3.4.21.-/PCSK9 protein, rat; EC 3.4.21.-/Serine Endopeptidases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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