Document Detail


Human urinary metabolomic profile of PPARalpha induced fatty acid beta-oxidation.
MedLine Citation:
PMID:  19569716     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Activation of the peroxisome proliferator-activated receptor alpha (PPARalpha) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARalpha activation and hence increased fatty acid beta-oxidation, healthy human volunteers were given fenofibrate orally for 2 weeks and their urine was profiled by UPLC-QTOFMS. Biomarkers identified by the machine learning algorithm random forests included significant depletion by day 14 of both pantothenic acid (>5-fold) and acetylcarnitine (>20-fold), observations that are consistent with known targets of PPARalpha including pantothenate kinase and genes encoding proteins involved in the transport and synthesis of acylcarnitines. It was also concluded that serum cholesterol (-12.7%), triglycerides (-25.6%), uric acid (-34.7%), together with urinary propylcarnitine (>10-fold), isobutyrylcarnitine (>2.5-fold), (S)-(+)-2-methylbutyrylcarnitine (5-fold), and isovalerylcarnitine (>5-fold) were all reduced by day 14. Specificity of these biomarkers as indicators of PPARalpha activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARalpha-induced fatty acid beta-oxidation in humans. This study illustrates the utility of a pharmacometabolomic approach to understand drug effects on lipid metabolism in both human populations and in inbred mouse models.
Authors:
Andrew D Patterson; Ondrej Slanar; Kristopher W Krausz; Fei Li; Constance C Höfer; Frantisek Perlík; Frank J Gonzalez; Jeffrey R Idle
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Intramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of proteome research     Volume:  8     ISSN:  1535-3893     ISO Abbreviation:  J. Proteome Res.     Publication Date:  2009 Sep 
Date Detail:
Created Date:  2009-09-04     Completed Date:  2009-12-24     Revised Date:  2013-06-02    
Medline Journal Info:
Nlm Unique ID:  101128775     Medline TA:  J Proteome Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4293-300     Citation Subset:  IM    
Affiliation:
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
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MeSH Terms
Descriptor/Qualifier:
Adult
Algorithms
Analysis of Variance
Animals
Artificial Intelligence
Biological Markers / urine
Carnitine / analogs & derivatives,  urine
Chromatography, High Pressure Liquid
Fatty Acids / analysis,  metabolism,  urine*
Female
Fenofibrate / pharmacology
Humans
Hypolipidemic Agents / pharmacology
Male
Mass Spectrometry
Metabolome / drug effects
Metabolomics / methods*
Mice
Mice, Inbred C57BL
PPAR alpha / urine*
Pantothenic Acid / urine
Urine / chemistry
Grant Support
ID/Acronym/Agency:
Z01 BC005562-20/BC/NCI NIH HHS; Z01 BC005708-16/BC/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/Fatty Acids; 0/Hypolipidemic Agents; 0/PPAR alpha; 49562-28-9/Fenofibrate; 541-15-1/Carnitine; 79-83-4/Pantothenic Acid
Comments/Corrections

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


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