Document Detail


Eicosapentaenoic acid improves hepatic steatosis independent of PPARα activation through inhibition of SREBP-1 maturation in mice.
MedLine Citation:
PMID:  20691165     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Eicosapentaenoic acid (EPA) in fish oil is known to improve hepatic steatosis. However, it remains unclear whether such action of EPA is actually caused by peroxisome proliferator-activated receptor α (PPARα) activation. To explore the contribution of PPARα to the effects of EPA itself, male wild-type and Ppara-null mice were fed a saturated fat diet for 16 weeks, and highly (>98%)-purified EPA was administered in the last 12 weeks. Furthermore, the changes caused by EPA treatment were compared to those elicited by fenofibrate (FF), a typical PPARα activator. A saturated fat diet caused macrovesicular steatosis in both genotypes. However, EPA ameliorated steatosis only in wild-type mice without PPARα activation, which was evidently different from numerous previous observations. Instead, EPA inhibited maturation of sterol-responsive element-binding protein (SREBP)-1 in the presence of PPARα through down-regulation of SREBP cleavage-activating protein and site-1 protease. Additionally, EPA suppressed fatty acid uptake and promoted hydrolysis of intrahepatic triglycerides in a PPARα-independent manner. These effects were distinct from those of fenofibrate. Although fenofibrate induced NAPDH oxidase and acyl-coenzyme A oxidase and significantly increased hepatic lipid peroxides, EPA caused PPARα-dependent induction of superoxide dismutases, probably contributing to a decrease in the lipid peroxides. These results firstly demonstrate detailed mechanisms of steatosis-ameliorating effects of EPA without PPARα activation and ensuing augmentation of hepatic oxidative stress.
Authors:
Naoki Tanaka; Xiuguo Zhang; Eiko Sugiyama; Hiroyuki Kono; Akira Horiuchi; Takero Nakajima; Hiroki Kanbe; Eiji Tanaka; Frank J Gonzalez; Toshifumi Aoyama
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Publication Detail:
Type:  Journal Article     Date:  2010-08-04
Journal Detail:
Title:  Biochemical pharmacology     Volume:  80     ISSN:  1873-2968     ISO Abbreviation:  Biochem. Pharmacol.     Publication Date:  2010 Nov 
Date Detail:
Created Date:  2010-09-29     Completed Date:  2010-10-28     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0101032     Medline TA:  Biochem Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1601-12     Citation Subset:  IM    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
Affiliation:
Department of Metabolic Regulation, Shinshu University Graduate School of Medicine, Japan. tanakan@mail.nih.gov
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MeSH Terms
Descriptor/Qualifier:
Animals
Dietary Fats / administration & dosage,  adverse effects
Disease Models, Animal
Eicosapentaenoic Acid / pharmacology,  therapeutic use*
Fatty Liver / drug therapy*,  etiology,  metabolism,  pathology
Genotype
Immunoblotting
Lipid Peroxidation / drug effects
Liver / drug effects,  metabolism,  pathology
Liver Function Tests
Male
Mice
Mice, Knockout
Oxidative Stress / drug effects
PPAR alpha / genetics,  metabolism*
Procetofen / pharmacology
Sterol Regulatory Element Binding Protein 1 / antagonists & inhibitors*
Chemical
Reg. No./Substance:
0/Dietary Fats; 0/PPAR alpha; 0/Srebf1 protein, mouse; 0/Sterol Regulatory Element Binding Protein 1; 1553-41-9/Eicosapentaenoic Acid; 49562-28-9/Procetofen

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


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