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Metabolic profiling of PPAR^–/– mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation

Liza Makowski^*,, Robert C. Noland^*,, Timothy R. Koves^*,,, Weibing Xing^*,, Olga R. Ilkayeva^*,, Michael J. Muehlbauer^*,, Robert D. Stevens^*, and Deborah M. Muoio^*,,,1

^* Division of Endocrinology, Metabolism, and Nutrition, and

Division of Geriatrics, Department of Medicine,

Department of Pharmacology and Cancer Biology, and

Sarah W. Stedman Nutrition and Metabolism Center, Duke University School of Medicine, Durham, North Carolina, USA

¹Correspondence: 4321 Medical Park Dr., Ste. 200, Durham, NC 27704, USA. E-mail: muoio{at}duke.edu

Peroxisome proliferator-activated receptor- (PPAR) is a master transcriptional regulator of β-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 PPAR^+/+ and PPAR^–/– mice. Compared to PPAR^+/+ animals, acylcarnitine profiles of PPAR^–/– 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 β-oxidation. Organic and amino acid profiles of starved PPAR^–/– mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPAR^–/– 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 PPAR^–/– 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.—Makowski, L., Noland, R. C., Koves, T. R., Xing, W., Ilkayeva, O. R., Muehlbauer, M. J., Stevens, R. D., Muoio, D. M. Metabolic profiling of PPAR^–/– mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.

Key Words: β-oxidation • metabolomics • liver • skeletal muscle • acylcarnitine • organic acid • starvation

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