PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation
PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation
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DOI：
10.1172/jci40905
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发表时间：
2010-10-01
影响因子：
15.9
通讯作者：
Goldberg, Ira J.
中科院分区：
文献类型：
--
作者：
Son, Ni-Huiping;Yu, Shuiqing;Goldberg, Ira J.
在人类和动物模型中，心脏中过量的脂质积累与心功能下降有关。原因尚不清楚，但一般认为这是由于细胞内脂质的毒性作用或过量脂肪酸氧化（FAO）造成的。代谢综合征患者心脏中PPAR γ表达增加，使用PPAR γ激动剂与心力衰竭有关。在这里，将心肌细胞PPAR γ过表达引起的扩张型心肌病小鼠与PPAR α缺陷小鼠杂交。令人惊讶的是，这种杂交导致了介导脂肪酸（FA）摄取/氧化和三酰甘油（TAG）合成的几个ppar调节基因的表达增强。虽然FA氧化和TAG液滴大小增加，但心脏功能得到保留，生存得到改善。心脏甘油三酯水平或潜在毒性脂质二酰基甘油（DAG）和神经酰胺水平没有明显下降。长链FA辅酶A （LCCoA）水平升高，酰基肉碱含量降低。PKC α和PKC δ的激活、凋亡、ROS水平和内质网应激的证据也减少了。因此，尽管DAG和神经酰胺水平升高，但脂质分配到储存和氧化可以逆转心脏脂质毒性，这表明其他有毒中间体如酰基肉碱在心脏脂质积累的毒性作用中起作用。
Excess lipid accumulation in the heart is associated with decreased cardiac function in humans and in animal models. The reasons are unclear, but this is generally believed to result from either toxic effects of intracellular lipids or excessive fatty acid oxidation (FAO). PPAR gamma expression is increased in the hearts of humans with metabolic syndrome, and use of PPAR gamma agonists is associated with heart failure. Here, mice with dilated cardiomyopathy due to cardiomyocyte PPAR gamma overexpression were crossed with PPAR alpha-deficient mice. Surprisingly, this cross led to enhanced expression of several PPAR-regulated genes that mediate fatty acid (FA) uptake/oxidation and triacylglycerol (TAG) synthesis. Although FA oxidation and TAG droplet size were increased, heart function was preserved and survival improved. There was no marked decrease in cardiac levels of triglyceride or the potentially toxic lipids diacylglycerol (DAG) and ceramide. However, long-chain FA coenzyme A (LCCoA) levels were increased, and acylcarnitine content was decreased. Activation of PKC alpha and PKC delta, apoptosis, ROS levels, and evidence of endoplasmic reticulum stress were also reduced. Thus, partitioning of lipid to storage and oxidation can reverse cardiolipotoxicity despite increased DAG and ceramide levels, suggesting a role for other toxic intermediates such as acylcarnitines in the toxic effects of lipid accumulation in the heart.