Metabolic profiling of PPARα-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation
Metabolic profiling of PPARα-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation
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DOI：
10.1096/fj.08-119420
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发表时间：
2009-02-01
期刊：
影响因子：
4.8
通讯作者：
Muoio, Deborah M.
中科院分区：
文献类型：
--
作者：
Makowski, Liza;Noland, Robert C.;Muoio, Deborah M.
过氧化物酶体增殖物激活受体-α（PPAR-alpha）是β-氧化的主要转录调节因子，也是降血脂药物的重要靶点。为了更深入地了解脂肪代谢受损的全身性后果，我们使用定量的、基于质谱的代谢分析来研究PPAR α（+/+）和PPAR α（-/-）小鼠的进食至禁食转变。与PPAR α（+/+）动物相比，PPAR α（-/-）小鼠的酰基肉毒碱谱显示血浆中长链物质的蓄积为2- 4倍，而血浆、肝脏和骨骼肌中短链物质的蓄积减少高达69%。这些结果反映了肉毒碱棕榈酰转移酶-1（一种催化β-氧化第一步的线粒体酶）下游的代谢瓶颈。饥饿的PPARalpha（-/-）小鼠的有机和氨基酸谱表明柠檬酸循环通量受损，尿素循环活性增强，氨基酸催化剂增加。PPAR α（-/-）小鼠血浆和组织中游离肉毒碱水平降低40-50%，这与参与肉毒碱生物合成和转运的基因的肝脏表达减少相对应。一周的口服肉毒碱补充剂赋予部分代谢恢复的PPARalpha（-/-）小鼠。总之，全面的代谢分析揭示了脂肪氧化缺陷的新生物标志物，同时也突出了补充肉毒碱作为代谢紊乱的治疗和诊断工具的潜在价值。马科夫斯基湖诺兰德河C.的方法，Koves，T. R.，邢文，伊尔卡耶瓦岛R.，Muehlbauer，M. J.，史蒂文斯河D、穆约角，巴西-地M. PPAR α（-/-）小鼠的代谢分析揭示了肉毒碱和氨基酸稳态的缺陷，口服肉毒碱补充剂可部分逆转这些缺陷。FASEB J. 23，586-604（2009）
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)