Patterson Andrew D, Slanar Ondrej, Krausz Kristopher W, Li Fei, Höfer Constance C, Perlík Frantisek, Gonzalez Frank J, Idle Jeffrey R
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
J Proteome Res. 2009 Sep;8(9):4293-300. doi: 10.1021/pr9004103.
Activation of the peroxisome proliferator-activated receptor alpha (PPARalpha) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARalpha activation and hence increased fatty acid beta-oxidation, healthy human volunteers were given fenofibrate orally for 2 weeks and their urine was profiled by UPLC-QTOFMS. Biomarkers identified by the machine learning algorithm random forests included significant depletion by day 14 of both pantothenic acid (>5-fold) and acetylcarnitine (>20-fold), observations that are consistent with known targets of PPARalpha including pantothenate kinase and genes encoding proteins involved in the transport and synthesis of acylcarnitines. It was also concluded that serum cholesterol (-12.7%), triglycerides (-25.6%), uric acid (-34.7%), together with urinary propylcarnitine (>10-fold), isobutyrylcarnitine (>2.5-fold), (S)-(+)-2-methylbutyrylcarnitine (5-fold), and isovalerylcarnitine (>5-fold) were all reduced by day 14. Specificity of these biomarkers as indicators of PPARalpha activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARalpha-induced fatty acid beta-oxidation in humans. This study illustrates the utility of a pharmacometabolomic approach to understand drug effects on lipid metabolism in both human populations and in inbred mouse models.
过氧化物酶体增殖物激活受体α（PPARα）的激活与脂肪酸分解代谢增加有关，并且是治疗高脂血症的常用靶点。为了鉴定PPARα激活以及由此增加的脂肪酸β-氧化的潜在内源性生物标志物，健康人类志愿者口服非诺贝特2周，并通过超高效液相色谱-四极杆飞行时间质谱联用仪（UPLC-QTOFMS）对其尿液进行分析。通过机器学习算法随机森林鉴定出的生物标志物包括，在第14天时泛酸（>5倍）和乙酰肉碱（>20倍）均显著减少，这些观察结果与PPARα的已知靶点一致，包括泛酸激酶以及编码参与酰基肉碱转运和合成的蛋白质的基因。研究还得出结论，到第14天时，血清胆固醇（-12.7%）、甘油三酯（-25.6%）、尿酸（-34.7%），以及尿丙酰肉碱（>10倍）、异丁酰肉碱（>2.5倍）、（S）-（+）-2-甲基丁酰肉碱（5倍）和异戊酰肉碱（>5倍）均有所降低。使用Ppara基因敲除小鼠证明了这些生物标志物作为PPARα激活指标的特异性。尿泛酸和酰基肉碱可能是PPARα诱导的人类脂肪酸β-氧化的有用指标。这项研究说明了药物代谢组学方法在理解药物对人群和近交系小鼠模型脂质代谢影响方面的实用性。
