Watkins Steven M, Reifsnyder Peter R, Pan Huei-ju, German J Bruce, Leiter Edward H
Lipomics Technologies, Inc, 2545 Boatman Ave, West Sacramento, CA 95691, USA.
J Lipid Res. 2002 Nov;43(11):1809-17. doi: 10.1194/jlr.m200169-jlr200.
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.
慢性病的成功治疗必须使代谢的目标方面正常化，同时不干扰维持健康所必需的其他代谢途径的调节。使用有限数量的单一疾病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。在本研究中，我们采用了对脂质代谢物的全面代谢组学评估，以确定过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮在2型糖尿病新小鼠模型中对结构脂质代谢的具体影响。饮食中添加罗格列酮（200 mg/kg饮食）可抑制肥胖（NZO×NON）F1雄性小鼠的2型糖尿病，但长期治疗会明显加剧肝脂肪变性。代谢组学数据显示，罗格列酮：i）导致低脂血症（通过调节肝脏与血浆之间的脂质交换），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）显著改变心脏中游离脂肪酸和心磷脂的代谢，v）引发脂肪组织中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，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潜力。
