Document Detail


Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity.
MedLine Citation:
PMID:  22904346     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
During cocaine-induced hepatotoxicity, lipid accumulation occurs prior to necrotic cell death in the liver. However, the exact influences of cocaine on the homeostasis of lipid metabolism remain largely unknown. In this study, the progression of subacute hepatotoxicity, including centrilobular necrosis in the liver and elevation of transaminase activity in serum, was observed in a three-day cocaine treatment, accompanying the disruption of triacylglycerol (TAG) turnover. Serum TAG level increased on day 1 of cocaine treatment but remained unchanged afterwards. In contrast, hepatic TAG level was elevated continuously during three days of cocaine treatment and was better correlated with the development of hepatotoxicity. Lipidomic analyses of serum and liver samples revealed time-dependent separation of the control and cocaine-treated mice in multivariate models, which was due to the accumulation of long-chain acylcarnitines together with the disturbances of many bioactive phospholipid species in the cocaine-treated mice. An in vitro function assay confirmed the progressive inhibition of mitochondrial fatty acid oxidation after the cocaine treatment. Cotreatment of fenofibrate significantly increased the expression of peroxisome proliferator-activated receptor α (PPARα)-targeted genes and the mitochondrial fatty acid oxidation activity in the cocaine-treated mice, resulting in the inhibition of cocaine-induced acylcarnitine accumulation and other hepatotoxic effects. Overall, the results from this lipidomics-guided study revealed that the inhibition of fatty acid oxidation plays an important role in cocaine-induced liver injury.
Authors:
Xiaolei Shi; Dan Yao; Blake A Gosnell; Chi Chen
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Publication Detail:
Type:  In Vitro; Journal Article; Research Support, N.I.H., Extramural     Date:  2012-08-19
Journal Detail:
Title:  Journal of lipid research     Volume:  53     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2012 Nov 
Date Detail:
Created Date:  2012-10-09     Completed Date:  2013-03-06     Revised Date:  2013-11-05    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2318-30     Citation Subset:  IM    
Affiliation:
Department of Food Science and Nutrition, University of Minnesota, St Paul, MN 55108, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Chromatography, Liquid
Cocaine / toxicity*
Drug-Induced Liver Injury / metabolism
Fatty Acids
Lipid Metabolism / drug effects*
Liver / drug effects*,  metabolism*
Male
Mass Spectrometry
Mice
Mice, Inbred C57BL
Oxidation-Reduction / drug effects
PPAR alpha / metabolism
Palmitoylcarnitine / metabolism
Grant Support
ID/Acronym/Agency:
5R21DA-027469/DA/NIDA NIH HHS; R21 DA027469/DA/NIDA NIH HHS
Chemical
Reg. No./Substance:
0/Fatty Acids; 0/PPAR alpha; 1935-18-8/Palmitoylcarnitine; 50-36-2/Cocaine
Comments/Corrections

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