| Lipidomic profiling reveals protective function of fatty acid oxidation in cocaine-induced hepatotoxicity. | |
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MedLine Citation:
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PMID: 22904346 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Xiaolei Shi; Dan Yao; Blake A Gosnell; Chi Chen |
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Publication Detail:
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Type: In Vitro; Journal Article; Research Support, N.I.H., Extramural Date: 2012-08-19 |
Journal Detail:
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Title: Journal of lipid research Volume: 53 ISSN: 0022-2275 ISO Abbreviation: J. Lipid Res. Publication Date: 2012 Nov |
Date Detail:
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Created Date: 2012-10-09 Completed Date: 2013-03-06 Revised Date: 2013-04-16 |
Medline Journal Info:
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Nlm Unique ID: 0376606 Medline TA: J Lipid Res Country: United States |
Other Details:
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Languages: eng Pagination: 2318-30 Citation Subset: IM |
Affiliation:
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Department of Food Science and Nutrition, University of Minnesota, St Paul, MN 55108, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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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:
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5R21DA-027469/DA/NIDA NIH HHS; R21 DA027469/DA/NIDA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids; 0/PPAR alpha; 1935-18-8/Palmitoylcarnitine; 50-36-2/Cocaine |
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