Metabolic profiling of PPARα −/− mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation
- 15 October 2008
- journal article
- research article
- Published by Wiley in The FASEB Journal
- Vol. 23 (2), 586-604
- https://doi.org/10.1096/fj.08-119420
Abstract
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.Keywords
Funding Information
- National Institutes of Health (P30‐AG028716, K99‐AA017376‐01, F32‐DK080609)
- American Diabetes Association
This publication has 70 references indexed in Scilit:
- Partial Resistance to Peroxisome Proliferator–Activated Receptor-α Agonists in ZDF Rats Is Associated With Defective Hepatic Mitochondrial MetabolismDiabetes, 2008
- Diet-induced obesity alters protein synthesis: tissue-specific effects in fasted versus fed miceMetabolism, 2008
- Grip strength and the metabolic syndrome: findings from the Hertfordshire Cohort StudyQJM: An International Journal of Medicine, 2007
- Cell-Permeating α-Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient CellsMolecular and Cellular Biology, 2007
- Hypoxia Inducible Factor Prolyl 4-Hydroxylase Enzymes: Center Stage in the Battle Against Hypoxia, Metabolic Compromise and Oxidative StressNeurochemical Research, 2007
- Sarcopenic obesity and inflammation in the InCHIANTI studyJournal of Applied Physiology, 2007
- Fuel Metabolism in StarvationAnnual Review of Nutrition, 2006
- Fenofibrate modifies transaminase gene expression via a peroxisome proliferator activated receptor α-dependent pathwayToxicology Letters, 1998
- A Novel Disease with Deficiency of Mitochondrial Very-Long-Chain Acyl-CoA DehydrogenaseBiochemical and Biophysical Research Communications, 1993
- Short-Chain Acyl-CoA Dehydrogenase Deficiency Associated with a Lipid-Storage Myopathy and Secondary Carnitine DeficiencyThe New England Journal of Medicine, 1984