Document Detail


Carvedilol attenuates the progression of alcohol fatty liver disease in rats.
MedLine Citation:
PMID:  22413959     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Hepatosteatosis is an essential step in liver disease progression. However, the mechanisms that mediate the progression of hepatosteatosis and the optimal inhibitor of them remain largely unclear. The sympathetic nervous system (SNS) is responsible for the lipid metabolism and the accumulation of collagen that occurs in an injured liver. Medicines that inhibit this pathway may be a relevant treatment for the hepatosteatosis, and then reduce the liver injury that progresses through the stage of steatosis to fibrosis.
METHODS: Using an ethanol-liquid-diet-fed rat model of alcohol fatty liver disease (AFLD), we studied the effects of carvedilol, which can block the SNS completely via β1, β2, and α1 adrenergic receptors, on the sympathetic tone, hepatosteatosis, and fibrosis based on histological, immunohistochemical, Western blot, and reverse transcriptase polymerase chain reaction analyses.
RESULTS: Carvedilol inhibited the ethanol-induced whole-body and hepatic sympathetic activities based on the serum 3-methoxy-4-hydroxyphenylglycol level and hepatic tyrosine hydroxylase expression. Carvedilol attenuated the hepatosteatosis, as evidenced by reduced hepatic triglyceride level and the accumulation of fatty droplets within hepatocytes, down-regulated fatty acid synthase and sterol regulatory element binding protein-1, and up-regulated peroxisome proliferator-activated receptor-α. No fibrosis signs were shown in our rat model. Carvedilol inhibited ethanol-induced the thickening of zone 3 vessel walls, reduced the activation of hepatic stellate cells (HSCs), and decreased the induction of collagen, transforming growth factor β1, and tissue inhibitor of metalloproteinases-1. Tumor necrosis factor α (TNF-α) was expressed on the activated HSCs and inhibited by carvedilol based on the immunohistochemical double staining analysis.
CONCLUSIONS: Ethanol metabolism-induced lipogenesis may trigger the SNS-activated HSCs feedback loop, and then induct the activated HSCs and the activated HSCs-derived TNF-α, the mediator of lipogenesis, overproduction. Carvedilol may block this feedback loop via antisympathetic activity and demonstrate its preventive role on the development of hepatosteatosis in rat with AFLD.
Authors:
Jinyao Liu; Izumi Takase; Ayako Hakucho; Nanako Okamura; Tatsuya Fujimiya
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-03-13
Journal Detail:
Title:  Alcoholism, clinical and experimental research     Volume:  36     ISSN:  1530-0277     ISO Abbreviation:  Alcohol. Clin. Exp. Res.     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-07     Completed Date:  2013-01-21     Revised Date:  2013-05-28    
Medline Journal Info:
Nlm Unique ID:  7707242     Medline TA:  Alcohol Clin Exp Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  1587-99     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 by the Research Society on Alcoholism.
Affiliation:
Department of Legal Medicine, Yamaguchi University Graduate School of Medicine, Ube, Japan. czhliu@yamaguchi-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Adrenergic beta-Antagonists / therapeutic use*
Animals
Blood Vessels / pathology
Blotting, Western
Carbazoles / therapeutic use*
Central Nervous System Depressants / blood
Disease Progression
Ethanol / blood
Fatty Liver, Alcoholic / drug therapy*,  pathology
Fluorescent Antibody Technique
Hepatic Stellate Cells / drug effects
Immunohistochemistry
Liver / metabolism
Liver Cirrhosis / genetics
Male
Methoxyhydroxyphenylglycol / metabolism
Propanolamines / therapeutic use*
Rats
Rats, Wistar
Real-Time Polymerase Chain Reaction
Sympathetic Nervous System / drug effects,  physiology
Triglycerides / metabolism
Tumor Necrosis Factor-alpha / antagonists & inhibitors,  biosynthesis
Chemical
Reg. No./Substance:
0/Adrenergic beta-Antagonists; 0/Carbazoles; 0/Central Nervous System Depressants; 0/Propanolamines; 0/Triglycerides; 0/Tumor Necrosis Factor-alpha; 0K47UL67F2/carvedilol; 534-82-7/Methoxyhydroxyphenylglycol; 64-17-5/Ethanol

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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