Wheelock Craig E, Goto Susumu, Hammock Bruce D, Newman John W
Department of Entomology and Cancer Research Center, University of California, Davis, CA 95616.
Metabolomics. 2007 Jun;3(2):137-145. doi: 10.1007/s11306-007-0052-8.
Peroxisome proliferator activated receptor alpha (PPARα) agonists are anti-hyperlipidemic drugs that influence fatty acid combustion, phospholipid biosynthesis and lipoprotein metabolism. To evaluate impacts on other aspects of lipid metabolism, we applied targeted metabolomics to liver, heart, brain and white adipose tissue samples from male Swiss-Webster mice exposed to a 5 day, 500 mg/kg/day regimen of i.p. clofibrate. Tissue concentrations of free fatty acids and the fatty acid content of sphingomyelin, cardiolipin, cholesterol esters, triglycerides and phospholipids were quantified. Responses were tissue-specific, with changes observed in the liver > heart ≫ brain > adipose. These results indicate that liver saturated fatty acid-rich triglycerides feeds clofibrate-induced monounsaturated fatty acid (MUFA) synthesis, which were incorporated into hepatic phospholipids and sphingomyelin. In addition, selective enrichment of docosahexeneoic acid in the phosphatidylserine of liver (1.7-fold), heart (1.6-fold) and brain (1.5-fold) suggests a clofibrate-dependent systemic activation of phosphatidylserine synthetase 2. Furthermore, the observed ~20% decline in cardiac sphingomyelin is consistent with activation of a sphingomeylinase with a substrate preference for polyunsaturate-containing sphingomyelin. Finally, perturbations in the liver, brain, and adipose cholesterol esters were observed, with clofibrate exposure elevating brain cholesterol arachidonyl-esters ~20-fold. Thus, while supporting previous findings, this study has identified novel impacts of PPARα agonist exposure on lipid metabolism that should be further explored.
过氧化物酶体增殖物激活受体α（PPARα）激动剂是一类抗高血脂药物，可影响脂肪酸燃烧、磷脂生物合成和脂蛋白代谢。为评估其对脂质代谢其他方面的影响，我们对雄性瑞士韦伯斯特小鼠进行了腹腔注射氯贝丁酯的实验，剂量为500mg/kg/天，持续5天，之后应用靶向代谢组学技术分析了肝脏、心脏、大脑和白色脂肪组织样本。对游离脂肪酸的组织浓度以及鞘磷脂、心磷脂、胆固醇酯、甘油三酯和磷脂中的脂肪酸含量进行了定量分析。结果显示，不同组织的反应具有特异性，肝脏中的变化最为明显，其次是心脏，大脑和脂肪组织中的变化相对较小。这些结果表明，肝脏中富含饱和脂肪酸的甘油三酯促进了氯贝丁酯诱导的单不饱和脂肪酸（MUFA）合成，这些单不饱和脂肪酸被整合到肝脏磷脂和鞘磷脂中。此外，肝脏、心脏和大脑的磷脂酰丝氨酸中二十二碳六烯酸的选择性富集（分别为1.7倍、1.6倍和1.5倍）表明，氯贝丁酯可依赖全身激活磷脂酰丝氨酸合成酶2。此外，观察到心脏鞘磷脂下降约20%，这与鞘磷脂酶的激活一致，该酶对含多不饱和脂肪酸的鞘磷脂具有底物偏好性。最后，观察到肝脏和大脑以及脂肪组织中的胆固醇酯出现扰动，氯贝丁酯暴露使大脑中的花生四烯酸胆固醇酯升高约20倍。因此，本研究在支持先前研究结果的同时，还发现了PPARα激动剂暴露对脂质代谢的新影响，值得进一步探索。
