期刊
FASEB JOURNAL
卷 23, 期 2, 页码 586-604出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.08-119420
关键词
beta-oxidation; metabolomics; liver; skeletal muscle; acylcarnitine; organic acid; starvation
资金
- National Institutes of Health [P30-AG028716, K99-AA017376-01, F32-DK080609]
- American Diabetes Association
- John A. Hartford Duke Center
Peroxisome proliferator-activated receptor-alpha (PPAR alpha) 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 PPAR alpha(+/+) and PPAR alpha(-/-) mice. Compared to PPAR alpha(+/+) animals, acylcarnitine profiles of PPAR alpha(-/-) 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 PPAR alpha(-/-) mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPAR alpha(-/-) 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 alpha(-/-) 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 alpha(-/-) mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation. FASEB J. 23, 586-604 (2009)
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