Human urinary metabolomic profile of PPARalpha induced fatty acid beta-oxidation.
Human urinary metabolomic profile of PPARalpha induced fatty acid beta-oxidation.
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DOI：
10.1021/pr9004103
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发表时间：
2009-09
影响因子：
4.4
通讯作者：
Idle, Jeffrey R.
中科院分区：
文献类型：
--
作者：
Patterson, Andrew D.;Slanar, Ondrej;Krausz, Kristopher W.;Li, Fei;Hoefer, Constance C.;Perlik, Frantisek;Gonzalez, Frank J.;Idle, Jeffrey R.
过氧化物酶体增殖物激活受体α（过氧化物酶体增殖物激活受体α）的激活与脂肪酸催化剂增加相关，通常用于治疗高脂血症。为了鉴定潜在的内源性PPARα活化生物标志物，从而增加脂肪酸β-氧化，健康志愿者口服非诺贝特2周，并通过UPLC-QTOFMS分析其尿液。通过机器学习算法随机森林识别的生物标志物包括到第14天泛酸（>5倍）和乙酰肉毒碱（>20倍）的显著消耗，观察结果与PPARα的已知靶点一致，包括泛酸激酶和编码参与酰基肉毒碱转运和合成的蛋白质的基因。还得出结论，到第14天，血清胆固醇（-12.7%）、甘油三酯（-25.6%）、尿酸（-34.7%）以及尿丙基肉碱（>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）均降低。使用Ppara缺失小鼠证明了这些生物标志物作为PPARα活化指标的特异性。尿泛酸和酰基肉毒碱可能是人体中PPARα诱导的脂肪酸β氧化的有用指标。本研究说明了药物代谢组学方法的效用，以了解药物对人群和近交系小鼠模型中脂质代谢的影响。
Activation of the peroxisome proliferator-activated receptor α (PPARα) is associated with increased fatty acid catabolism and is commonly targeted for the treatment of hyperlipidemia. To identify latent, endogenous biomarkers of PPARα activation and hence increased fatty acid β-oxidation, healthy human volunteers were given fenofibrate orally for 2 weeks and their urine 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 PPARα 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 PPARα activation was demonstrated using the Ppara-null mouse. Urinary pantothenic acid and acylcarnitines may prove useful indicators of PPARα-induced fatty acid β-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.
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影响因子：
4.8
作者：
Guerre-Millo, M;Gervois, P;Staels, B
通讯作者：
Staels, B
影响因子：
2.6
作者：
Connor, SC;Hodson, MP;Haselden, JN
通讯作者：
Haselden, JN
影响因子：
6.1
作者：
Delaney, J;Hodson, MP;Waterfield, CJ
通讯作者：
Waterfield, CJ
影响因子：
12.3
作者：
Eichler GS;Reimers M;Kane D;Weinstein JN
通讯作者：
Weinstein JN
影响因子：
2.6
作者：
Ringeissen, S;Connor, SC;Waterfield, CJ
通讯作者：
Waterfield, CJ