PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling.
PPAR-pan activation induces hepatic oxidative stress and lipidomic remodelling.
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DOI：
10.1016/j.freeradbiomed.2015.11.033
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发表时间：
2016-06
影响因子：
7.4
通讯作者：
Griffin JL
中科院分区：
文献类型：
--
作者：
Ament Z;West JA;Stanley E;Ashmore T;Roberts LD;Wright J;Nicholls AW;Griffin JL
过氧化物酶体增殖物激活受体(PPAR)是一种配体激活的核受体，调节细胞的稳态和代谢。PPAR控制与脂肪酸和脂肪代谢有关的基因的表达。尽管有证据表明，PPAR激动剂在治疗代谢性疾病，特别是血脂异常和2型糖尿病方面具有良好的效果，但PPAR激动剂也与各种副作用和不利的病理变化有关。已经开发出同时激活三种PPAR受体(PPAR、α，γ和δ)的激动剂，希望能够在利用有益作用的同时避免一些负面副作用。本研究观察了停用的PPAR-PAN激动剂(PPAR-α，-γ和-δ的三重激动剂)对雄性SD大鼠饮食治疗后肝脏的影响。该激动剂诱导肝脏增大，并伴随着代谢和脂类重塑。与氧化过程有关的几种代谢物，如氧甲硫氨酸、甲基胞嘧啶和腺苷甲硫氨酸的浓度增加，表明应激和免疫状态增加。这些变化反映在脂肪的变化和能量需求的增加上，如自由脂肪酸(18：3n−3，20：5n−3减少和n−6/n−3脂肪酸比率增加)、三酰甘油、磷脂(体积变化分别减少和增加)和二十烷类化合物含量(PGB2和15-脱氧PGJ2增加)。我们得出结论，被研究的PPAR激动剂GW625019可诱导肝脏增大，伴随着脂体重塑、氧化应激和几种促炎二十烷类化合物的增加。这表明，应该在药物开发过程中监测这些途径，并概述PPAR激动剂如何诱导肝脏增殖。所研究的PPAR-PAN激动剂增加了大鼠肝脏的氧化损伤。代谢组学可以用来跟踪PPAR-PAN激动剂的剂量反应性质。代谢组学是跟踪氧化应激的一种通用工具。
The peroxisome proliferator-activated receptors (PPARs) are ligand activated nuclear receptors that regulate cellular homoeostasis and metabolism. PPARs control the expression of genes involved in fatty-acid and lipid metabolism. Despite evidence showing beneficial effects of their activation in the treatment of metabolic diseases, particularly dyslipidaemias and type 2 diabetes, PPAR agonists have also been associated with a variety of side effects and adverse pathological changes. Agonists have been developed that simultaneously activate the three PPAR receptors (PPARα, γ and δ) in the hope that the beneficial effects can be harnessed while avoiding some of the negative side effects. In this study, the hepatic effects of a discontinued PPAR-pan agonist (a triple agonist of PPAR-α, -γ, and -δ), was investigated after dietary treatment of male Sprague–Dawley (SD) rats. The agonist induced liver enlargement in conjunction with metabolomic and lipidomic remodelling. Increased concentrations of several metabolites related to processes of oxidation, such as oxo-methionine, methyl-cytosine and adenosyl-methionine indicated increased stress and immune status. These changes are reflected in lipidomic changes, and increased energy demands as determined by free fatty acid (decreased 18:3 n−3, 20:5 n−3 and increased ratios of n−6/n−3 fatty acids) triacylglycerol, phospholipid (decreased and increased bulk changes respectively) and eicosanoid content (increases in PGB2 and 15-deoxy PGJ2). We conclude that the investigated PPAR agonist, GW625019, induces liver enlargement, accompanied by lipidomic remodelling, oxidative stress and increases in several pro-inflammatory eicosanoids. This suggests that such pathways should be monitored in the drug development process and also outline how PPAR agonists induce liver proliferation. The investigated PPAR-pan agonist increased oxidative damage in the rat liver. Metabolomics can be used to follow the dose response nature of PPAR-pan agonists. Metabolomics is a versatile tool in following oxidative stress.