DISORDER OF CARNITINE METABOLISM AND LIPD SIGNAL TRANSDUCTION IN MYOCARDIUM

内脏脂肪变性（JVS）小鼠，一种由肉毒碱转运突变引起的全身性肉毒碱缺乏症的遗传模型，发生心脏肥大。我们确定了两个假定的脂质信使，1，2-二酰基甘油（DAG）和神经酰胺，在JVS和肉毒碱棕榈酰转移酶-I（CPT-I）抑制剂依托莫西治疗的小鼠，因为这些脂质的功能作为共同信使在心肌通过修改蛋白激酶C活性。在4周龄和8周龄时评价JVS小鼠。在4至8周龄的对照小鼠中研究了长期依托莫西治疗对小鼠的影响。作为抑制的心脏肥大的模型，产生肉毒碱处理的JVS（CT）小鼠。测定心肌DAG和神经酰胺水平及其脂肪酸组成。与对照组相比，JVS小鼠的心脏/体重比增加了100%，而CT小鼠的心脏/体重比在8周龄时与对照组相比正常化。与对照组相比，JVS和依托莫西治疗组小鼠的DAG均显著增加，而CT组小鼠的DAG则显著降低。此外，DAG的脂肪酸组成是相似的JVS和莫西尔处理的小鼠之间，特别是，18：1和18：2在心肌中显着升高。而CT小鼠的DAG与对照组相似。相比之下，各组间心肌神经酰胺水平无差异。依托莫西的药理学干预模拟遗传JVS小鼠脂质第二信使特征的变化。结果表明，不同DAG种类的增加可能参与了脂肪酸转运障碍导致的心肌肥大的发病机制。

The visceral steatosis (JVS) mouse, a genetic model of systemic carnitine deficiency resulting from carnitine transport mutation, develops cardiac hypertrophy. We determined two putative lipid messengers, 1,2-diacylglycerol (DAG) and ceramide, in JVS and carnitine palmitoyltransferase-I (CPT-I) inhibitor etomoxir-treated mice because these lipids function as co-messengers in the myocardium via modification of protein kinase C activity. JVS mice were evaluated at 4 and 8 weeks of age. The effect of long-term etomoxir treatment on mice was investigated in control mice from 4 to 8 weeks of age. As a model of inhibited cardiac hypertrophy, carnitine-treated JVS (CT) mice were produced. Myocardial DAG and ceramide levels, and their fatty acid composition were measured. The heart/body weight ratio increased by 100% in JVS mice compared with that in controls, while that of CT mice was normalized in comparison with controls at 8 weeks of age. DAG markedly increased in both JVS and etomoxir-treated mice compared with that in controls, whereas it was decreased significantly in CT mice compared with that in JVS mice. Furthermore, the fatty acid composition of DAG was similar between JVS and moxir-treated mice ; in particular, 18:1 and 18:2 were significantly elevated in the myocardium. On the other hand, that of DAG in CT mice was similar to that of the control group. In contrast, no difference was observed in myocardial ceramide levels among the groups. Pharmacological intervention of etomoxir mimics changes in the lipid second messenger characteristic of genetic JVS mice. The results suggest that the increases in distinct DAG species might be involved in the pathogenesis of cardiac hypertrophy as a result of disorder of fatty acid transport.