Cardiovascular Research Centre, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada.
Am J Physiol Endocrinol Metab. 2012 Dec 15;303(12):E1459-68. doi: 10.1152/ajpendo.00018.2012. Epub 2012 Oct 16.
We previously showed that genetic inactivation of malonyl-CoA decarboxylase (MCD), which regulates fatty acid oxidation, protects mice against high-fat diet-induced insulin resistance. Development of insulin resistance has been associated with activation of the inflammatory response. Therefore, we hypothesized that the protective effect of MCD inhibition might be caused by a favorable effect on the inflammatory response. We examined if pharmacological inhibition of MCD protects neonatal cardiomyocytes and peritoneal macrophages against inflammatory-induced metabolic perturbations. Cardiomyocytes and macrophages were treated with LPS to induce an inflammatory response, in the presence or absence of an MCD inhibitor (CBM-301106, 10 μM). Inhibition of MCD attenuated the LPS-induced inflammatory response in cardiomyocytes and macrophages. MCD inhibition also prevented LPS impairment of insulin-stimulated glucose uptake in cardiomyocytes and increased phosphorylation of Akt. Additionally, inhibition of MCD strongly diminished LPS-induced activation of palmitate oxidation. We also found that treatment with an MCD inhibitor prevented LPS-induced collapse of total cellular antioxidant capacity. Interestingly, treatment with LPS or an MCD inhibitor did not alter intracellular triacylglycerol content. Furthermore, inhibition of MCD prevented LPS-induced increases in the level of ceramide in cardiomyocytes and macrophages while also ameliorating LPS-initiated decreases in PPAR binding. This suggests that the anti-inflammatory effect of MCD inhibition is mediated via accumulation of long-chain acyl-CoA, which in turn stimulates PPAR binding. Our results also demonstrate that pharmacological inhibition of MCD is a novel and promising approach to treat insulin resistance and its associated metabolic complications.
我们之前的研究表明，调节脂肪酸氧化的丙二酰辅酶 A 脱羧酶（MCD）的基因失活可保护小鼠免受高脂饮食诱导的胰岛素抵抗。胰岛素抵抗的发展与炎症反应的激活有关。因此，我们假设 MCD 抑制的保护作用可能是由于对炎症反应产生了有利影响。我们研究了 MCD 抑制剂是否可保护新生心肌细胞和腹腔巨噬细胞免受炎症引起的代谢紊乱。用 LPS 处理心肌细胞和巨噬细胞以诱导炎症反应，同时存在或不存在 MCD 抑制剂（CBM-301106，10 μM）。MCD 抑制可减弱 LPS 诱导的心肌细胞和巨噬细胞中的炎症反应。MCD 抑制还可防止 LPS 损害心肌细胞中胰岛素刺激的葡萄糖摄取，并增加 Akt 的磷酸化。此外，MCD 抑制可强烈抑制 LPS 诱导的棕榈酸氧化激活。我们还发现，用 MCD 抑制剂处理可防止 LPS 诱导的总细胞抗氧化能力崩溃。有趣的是，用 LPS 或 MCD 抑制剂处理不会改变细胞内三酰基甘油含量。此外，MCD 抑制可防止 LPS 诱导的心肌细胞和巨噬细胞中神经酰胺水平升高，同时改善 LPS 引发的 PPAR 结合减少。这表明 MCD 抑制的抗炎作用是通过长链酰基辅酶 A 的积累介导的，而长链酰基辅酶 A 反过来又刺激 PPAR 结合。我们的结果还表明，MCD 的药理学抑制是治疗胰岛素抵抗及其相关代谢并发症的一种新的有前途的方法。
