Document Detail


Inhibition of p53 attenuates steatosis and liver injury in a mouse model of non-alcoholic fatty liver disease.
MedLine Citation:
PMID:  23211317     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND & AIMS: p53 and its transcriptional target miRNA34a have been implicated in the pathogenesis of fatty liver. We tested the efficacy of a p53 inhibitor, pifithrin-α p-nitro (PFT) in attenuating steatosis, associated oxidative stress and apoptosis in a murine model of non-alcoholic fatty liver disease (NAFLD).
METHODS: C57BL/6 mice were fed a high-fat (HFD) or control diet for 8 weeks; PFT or DMSO (vehicle) was administered three times per week. Markers of oxidative stress and apoptosis as well as mediators of hepatic fatty acid metabolism were assessed by immunohistochemistry, Western blot, real-time PCR, and biochemical assays.
RESULTS: PFT administration suppressed HFD-induced weight gain, ALT elevation, steatosis, oxidative stress, and apoptosis. PFT treatment blunted the HFD-induced upregulation of miRNA34a and increased SIRT1 expression. In the livers of HFD-fed, PFT-treated mice, activation of the SIRT1/PGC1α/PPARα axis increased the expression of malonyl-CoA decarboxylase (MLYCD), an enzyme responsible for malonyl-CoA (mCoA) degradation. Additionally, the SIRT1/LKB1/AMPK pathway (upstream activator of MLYCD) was promoted by PFT. Thus, induction of these two pathways by PFT diminished the hepatic mCoA content by enhancing MLYCD expression and function. Since mCoA inhibits carnitine palmitoyltransferase 1 (CPT1), the decrease of hepatic mCoA in the PFT-treated, HFD-fed mice increased CPT1 activity, favored fatty acid oxidation, and decreased steatosis. Additionally, we demonstrated that PFT abrogated steatosis and promoted MLYCD expression in palmitoleic acid-treated human HepaRG cells.
CONCLUSIONS: The p53 inhibitor PFT diminished hepatic triglyceride accumulation and lipotoxicity in mice fed a HFD, by depleting mCoA and favoring the β-oxidation of fatty acids.
Authors:
Zoltan Derdak; Kristine A Villegas; Ragheb Harb; Annie M Wu; Aryanna Sousa; Jack R Wands
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-12-02
Journal Detail:
Title:  Journal of hepatology     Volume:  58     ISSN:  1600-0641     ISO Abbreviation:  J. Hepatol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-29     Completed Date:  2014-01-21     Revised Date:  2014-04-02    
Medline Journal Info:
Nlm Unique ID:  8503886     Medline TA:  J Hepatol     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  785-91     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Alanine Transaminase / metabolism
Animals
Apoptosis / drug effects
Benzothiazoles / pharmacology*
Cell Line
Diet, High-Fat / adverse effects
Disease Models, Animal
Fatty Acids / metabolism
Fatty Liver / metabolism,  pathology,  prevention & control*
Humans
Liver / drug effects,  metabolism,  pathology
Male
Malonyl Coenzyme A / metabolism
Mice
Mice, Inbred C57BL
MicroRNAs / genetics,  metabolism
Models, Biological
Oxidative Stress / drug effects
Toluene / analogs & derivatives*,  pharmacology
Triglycerides / metabolism
Tumor Suppressor Protein p53 / antagonists & inhibitors*,  metabolism
Weight Gain / drug effects
Grant Support
ID/Acronym/Agency:
R01 AA008169/AA/NIAAA NIH HHS; R01 CA123544/CA/NCI NIH HHS; R01AA08169/AA/NIAAA NIH HHS; R01CA123544/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Benzothiazoles; 0/Fatty Acids; 0/MIRN34 microRNA, mouse; 0/MicroRNAs; 0/Triglycerides; 0/Tumor Suppressor Protein p53; 0/pifithrin; 3FPU23BG52/Toluene; 524-14-1/Malonyl Coenzyme A; EC 2.6.1.2/Alanine Transaminase
Comments/Corrections

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


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