Human urinary metabolomic profile of PPARRα induced fatty acid β-oxidation

Andrew David Patterson, Ondřej Slanař, Kristopher W. Krausz, Fei Li, Constance C. Höfer, František Perlík, Frank J. Gonzalez, Jeffrey R. Idle

Research output: Contribution to journalArticle

43 Citations (Scopus)

Abstract

Activation of the peroxisome proliferator-activated receptor R (PPARR) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARα activation and hence increased fatty acid β-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 PPARR 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 PPARα activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARα-induced fatty acid β-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.

Original languageEnglish (US)
Pages (from-to)4293-4300
Number of pages8
JournalJournal of Proteome Research
Volume8
Issue number9
DOIs
StatePublished - Oct 19 2009

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Peroxisome Proliferator-Activated Receptors
Metabolomics
Fatty Acids
Biomarkers
Oxidation
Pantothenic Acid
Chemical activation
Acetylcarnitine
Fenofibrate
Gene encoding
Hyperlipidemias
Uric Acid
Lipid Metabolism
Learning algorithms
Learning systems
Healthy Volunteers
Triglycerides
Cholesterol
Urine
Serum

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Chemistry(all)

Cite this

Patterson, A. D., Slanař, O., Krausz, K. W., Li, F., Höfer, C. C., Perlík, F., ... Idle, J. R. (2009). Human urinary metabolomic profile of PPARRα induced fatty acid β-oxidation. Journal of Proteome Research, 8(9), 4293-4300. https://doi.org/10.1021/pr9004103
Patterson, Andrew David ; Slanař, Ondřej ; Krausz, Kristopher W. ; Li, Fei ; Höfer, Constance C. ; Perlík, František ; Gonzalez, Frank J. ; Idle, Jeffrey R. / Human urinary metabolomic profile of PPARRα induced fatty acid β-oxidation. In: Journal of Proteome Research. 2009 ; Vol. 8, No. 9. pp. 4293-4300.
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Patterson, AD, Slanař, O, Krausz, KW, Li, F, Höfer, CC, Perlík, F, Gonzalez, FJ & Idle, JR 2009, 'Human urinary metabolomic profile of PPARRα induced fatty acid β-oxidation', Journal of Proteome Research, vol. 8, no. 9, pp. 4293-4300. https://doi.org/10.1021/pr9004103

Human urinary metabolomic profile of PPARRα induced fatty acid β-oxidation. / Patterson, Andrew David; Slanař, Ondřej; Krausz, Kristopher W.; Li, Fei; Höfer, Constance C.; Perlík, František; Gonzalez, Frank J.; Idle, Jeffrey R.

In: Journal of Proteome Research, Vol. 8, No. 9, 19.10.2009, p. 4293-4300.

Research output: Contribution to journalArticle

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T1 - Human urinary metabolomic profile of PPARRα induced fatty acid β-oxidation

AU - Patterson, Andrew David

AU - Slanař, Ondřej

AU - Krausz, Kristopher W.

AU - Li, Fei

AU - Höfer, Constance C.

AU - Perlík, František

AU - Gonzalez, Frank J.

AU - Idle, Jeffrey R.

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N2 - Activation of the peroxisome proliferator-activated receptor R (PPARR) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARα activation and hence increased fatty acid β-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 PPARR 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 PPARα activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARα-induced fatty acid β-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.

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