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Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.

Publication ,  Journal Article
Makowski, L; Noland, RC; Koves, TR; Xing, W; Ilkayeva, OR; Muehlbauer, MJ; Stevens, RD; Muoio, DM
Published in: FASEB J
February 2009

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a master transcriptional regulator of beta-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used quantitative, mass spectrometry-based metabolic profiling to investigate the fed-to-fasted transition in PPARalpha(+/+) and PPARalpha(-/-) mice. Compared to PPARalpha(+/+) animals, acylcarnitine profiles of PPARalpha(-/-) mice revealed 2- to 4-fold accumulation of long-chain species in the plasma, whereas short-chain species were reduced by as much as 69% in plasma, liver, and skeletal muscle. These results reflect a metabolic bottleneck downstream of carnitine palmitoyltransferase-1, a mitochondrial enzyme that catalyzes the first step in beta-oxidation. Organic and amino acid profiles of starved PPARalpha(-/-) mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPARalpha(-/-) mice had 40-50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARalpha(-/-) mice. In summary, comprehensive metabolic profiling revealed novel biomarkers of defective fat oxidation, while also highlighting the potential value of supplemental carnitine as a therapy and diagnostic tool for metabolic disorders.

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Published In

FASEB J

DOI

EISSN

1530-6860

Publication Date

February 2009

Volume

23

Issue

2

Start / End Page

586 / 604

Location

United States

Related Subject Headings

  • PPAR alpha
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Metabolome
  • Male
  • Hot Temperature
  • Homeostasis
  • Carnitine
  • Biochemistry & Molecular Biology
 

Citation

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Makowski, L., Noland, R. C., Koves, T. R., Xing, W., Ilkayeva, O. R., Muehlbauer, M. J., … Muoio, D. M. (2009). Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation. FASEB J, 23(2), 586–604. https://doi.org/10.1096/fj.08-119420
Makowski, Liza, Robert C. Noland, Timothy R. Koves, Weibing Xing, Olga R. Ilkayeva, Michael J. Muehlbauer, Robert D. Stevens, and Deborah M. Muoio. “Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.FASEB J 23, no. 2 (February 2009): 586–604. https://doi.org/10.1096/fj.08-119420.
Makowski L, Noland RC, Koves TR, Xing W, Ilkayeva OR, Muehlbauer MJ, et al. Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation. FASEB J. 2009 Feb;23(2):586–604.
Makowski, Liza, et al. “Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.FASEB J, vol. 23, no. 2, Feb. 2009, pp. 586–604. Pubmed, doi:10.1096/fj.08-119420.
Makowski L, Noland RC, Koves TR, Xing W, Ilkayeva OR, Muehlbauer MJ, Stevens RD, Muoio DM. Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation. FASEB J. 2009 Feb;23(2):586–604.

Published In

FASEB J

DOI

EISSN

1530-6860

Publication Date

February 2009

Volume

23

Issue

2

Start / End Page

586 / 604

Location

United States

Related Subject Headings

  • PPAR alpha
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • Metabolome
  • Male
  • Hot Temperature
  • Homeostasis
  • Carnitine
  • Biochemistry & Molecular Biology