Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.
Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone.
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发表时间：
2002
影响因子：
6.5
通讯作者：
S. Watkins;Peter R. Reifsnyder;Huei-ju Pan;J. German;E. Leiter
中科院分区：
文献类型：
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作者：
S. Watkins;Peter R. Reifsnyder;Huei-ju Pan;J. German;E. Leiter
慢性病的成功治疗必须使代谢的目标方面正常化，而不破坏对维持健康至关重要的其他代谢途径的调节。使用有限数量的疾病单分子替代物或生物标志物来监测治疗效果可能无法预测不良副作用。在这项研究中，采用脂质代谢物的综合代谢组学评估来确定过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮对新型2型糖尿病小鼠模型中结构脂质代谢的具体影响。饮食补充罗格列酮（200 mg/kg 饮食）可抑制肥胖 (NZO x NON)F1 雄性小鼠的 2 型糖尿病，但长期治疗会显着加剧肝脏脂肪变性。代谢组学数据显示，罗格列酮 i) 诱导低脂血症（通过调节肝脏-血浆脂质交换），ii) 诱导脂肪酸从头合成，iii) 减少过氧化物酶体内脂质的生物合成，iv) 显着改变心脏中的游离脂肪酸和心磷脂代谢，v) 引起脂肪组织内多不饱和脂肪酸的异常积累。这些观察结果表明罗格列酮诱导的表型是由多种组织特异性代谢变量介导的。由于罗格列酮对组织代谢的许多影响都反映在血浆脂质代谢组中，因此代谢组学在开发药物治疗代谢反应的临床评估方面具有巨大的潜力。
Successful therapy for chronic diseases must normalize a targeted aspect of metabolism without disrupting the regulation of other metabolic pathways essential for maintaining health. Use of a limited number of single molecule surrogates for disease, or biomarkers, to monitor the efficacy of a therapy may fail to predict undesirable side effects. In this study, a comprehensive metabolomic assessment of lipid metabolites was employed to determine the specific effects of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonist rosiglitazone on structural lipid metabolism in a new mouse model of Type 2 diabetes. Dietary supplementation with rosiglitazone (200 mg/kg diet) suppressed Type 2 diabetes in obese (NZO x NON)F1 male mice, but chronic treatment markedly exacerbated hepatic steatosis. The metabolomic data revealed that rosiglitazone i) induced hypolipidemia (by dysregulating liver-plasma lipid exchange), ii) induced de novo fatty acid synthesis, iii) decreased the biosynthesis of lipids within the peroxisome, iv) substantially altered free fatty acid and cardiolipin metabolism in heart, and v) elicited an unusual accumulation of polyunsaturated fatty acids within adipose tissue. These observations suggest that the phenotypes induced by rosiglitazone are mediated by multiple tissue-specific metabolic variables. Because many of the effects of rosiglitazone on tissue metabolism were reflected in the plasma lipid metabolome, metabolomics has excellent potential for developing clinical assessments of metabolic response to drug therapy.