Increased Mitochondrial Fatty Acid Oxidation Is Sufficient to Protect Skeletal Muscle Cells from Palmitate-induced Apoptosis
Increased Mitochondrial Fatty Acid Oxidation Is Sufficient to Protect Skeletal Muscle Cells from Palmitate-induced Apoptosis
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DOI：
10.1074/jbc.m110.170431
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发表时间：
2010-11-19
影响因子：
4.8
通讯作者：
Cohen, Isabelle
中科院分区：
文献类型：
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作者：
Henique, Carole;Mansouri, Abdelhak;Cohen, Isabelle
单不饱和脂肪酸（如油酸酯）对骨骼肌细胞中饱和脂肪酸（如棕榈酸酯）脂毒作用的保护作用机制仍知之甚少。本研究旨在研究线粒体长链脂肪酸（LCFA）氧化介导油酸对棕榈酸诱导的脂毒性的保护作用。CPT 1（carnitine palmitoyltransferase 1）是线粒体LCFA氧化的关键调节酶，可被脂肪生成的中间产物丙二酰辅酶A（malonyl-CoA）抑制。我们发现，在C2 C12肌管中表达的突变形式的CPT 1（CPT 1 mt），这是积极的，但不敏感的丙二酰辅酶A抑制，导致增加LCFA氧化通量，即使在存在高浓度的葡萄糖和胰岛素。此外，与油酸预孵育相似，CPT 1 mt表达通过降低有害棕榈酸酯衍生物（即二酰基甘油和神经酰胺）的含量来保护肌细胞免受棕榈酸酯诱导的细胞凋亡和胰岛素抵抗。油酸预孵育通过两种机制发挥其保护作用：（i）与CPT 1 mt表达相反，油酸预孵育增加棕榈酸向甘油三酯的通道，作为增强二酰基甘油酰基转移酶2表达的结果，和（ii）油酸预孵育通过增加CPT 1表达和调节乙酰辅酶A羧化酶和AMP活化蛋白激酶的活性促进棕榈酸氧化。总之，我们证明了通过CPT 1 mt表达靶向线粒体LCFA氧化导致与油酸酯预孵育相同的保护作用，提供了强有力的证据，即将棕榈酸酯代谢转向氧化足以保护免受棕榈酸酯诱导的脂毒性。
The mechanisms underlying the protective effect of mono-unsaturated fatty acids (e.g. oleate) against the lipotoxic action of saturated fatty acids (e.g. palmitate) in skeletal muscle cells remain poorly understood. This study aimed to examine the role of mitochondrial long-chain fatty acid (LCFA) oxidation in mediating oleate's protective effect against palmitate-induced lipotoxicity. CPT1 (carnitine palmitoyltransferase 1), which is the key regulatory enzyme of mitochondrial LCFA oxidation, is inhibited by malonyl-CoA, an intermediate of lipogenesis. We showed that expression of a mutant form of CPT1 (CPT1mt), which is active but insensitive to malonyl-CoA inhibition, in C2C12 myotubes led to increased LCFA oxidation flux even in the presence of high concentrations of glucose and insulin. Furthermore, similar to preincubation with oleate, CPT1mt expression protected muscle cells from palmitate-induced apoptosis and insulin resistance by decreasing the content of deleterious palmitate derivates (i.e. diacylglycerols and ceramides). Oleate preincubation exerted its protective effect by two mechanisms: (i) in contrast to CPT1mt expression, oleate preincubation increased the channeling of palmitate toward triglycerides, as a result of enhanced diacylglycerol acyltransferase 2 expression, and (ii) oleate preincubation promoted palmitate oxidation through increasing CPT1 expression and modulating the activities of acetyl-CoA carboxylase and AMP-activated protein kinase. In conclusion, we demonstrated that targeting mitochondrial LCFA oxidation via CPT1mt expression leads to the same protective effect as oleate preincubation, providing strong evidence that redirecting palmitate metabolism toward oxidation is sufficient to protect against palmitate-induced lipotoxicity.