Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
J Biol Chem. 2011 Sep 16;286(37):32045-53. doi: 10.1074/jbc.M111.285650. Epub 2011 Aug 2.
We examined the effects of adipose triglyceride lipase (ATGL) on the initiation of atherosclerosis. ATGL was recently identified as a rate-limiting triglyceride (TG) lipase. Mutations in the human ATGL gene are associated with neutral lipid storage disease with myopathy, a rare genetic disease characterized by excessive accumulation of TG in multiple tissues. The cardiac phenotype, known as triglyceride deposit cardiomyovasculopathy, shows massive TG accumulation in both coronary atherosclerotic lesions and the myocardium. Recent reports show that myocardial triglyceride content is significantly higher in patients with prediabetes or diabetes and that ATGL expression is decreased in the obese insulin-resistant state. Therefore, we investigated the effect of decreased ATGL activity on the development of atherosclerosis using human aortic endothelial cells. We found that ATGL knockdown enhanced monocyte adhesion via increased expression of TNFα-induced intercellular adhesion molecule-1 (ICAM-1). Next, we determined the pathways (MAPK, PKC, or NFκB) involved in ICAM-1 up-regulation induced by ATGL knockdown. Both phosphorylation of PKC and degradation of IκBα were increased in ATGL knockdown human aortic endothelial cells. In addition, intracellular diacylglycerol levels and free fatty acid uptake via CD36 were significantly increased in these cells. Inhibition of the PKC pathway using calphostin C and GF109203X suppressed TNFα-induced ICAM-1 expression. In conclusion, we showed that ATGL knockdown increased monocyte adhesion to the endothelium through enhanced TNFα-induced ICAM-1 expression via activation of NFκB and PKC. These results suggest that reduced ATGL expression may influence the atherogenic process in neutral lipid storage diseases and in the insulin-resistant state.
我们研究了脂肪甘油三酯脂肪酶 (ATGL) 对动脉粥样硬化起始的影响。ATGL 最近被鉴定为限速甘油三酯 (TG) 脂肪酶。人类 ATGL 基因突变与伴有肌病的中性脂肪贮积病有关，这是一种罕见的遗传性疾病，其特征是多种组织中 TG 的过度积累。心脏表型，即甘油三酯沉积性心肌病血管病，在冠状动脉粥样硬化病变和心肌中均显示出大量 TG 积累。最近的报告显示，前驱糖尿病或糖尿病患者的心肌甘油三酯含量明显更高，肥胖的胰岛素抵抗状态下 ATGL 的表达降低。因此，我们使用人主动脉内皮细胞研究了 ATGL 活性降低对动脉粥样硬化发展的影响。我们发现，ATGL 敲低通过增加 TNFα 诱导的细胞间黏附分子-1 (ICAM-1) 的表达增强单核细胞黏附。接下来，我们确定了 ATGL 敲低诱导 ICAM-1 上调所涉及的途径（MAPK、PKC 或 NFκB）。ATGL 敲低的人主动脉内皮细胞中 PKC 的磷酸化和 IκBα 的降解均增加。此外，这些细胞中的二酰基甘油水平和通过 CD36 的游离脂肪酸摄取显著增加。使用 calphostin C 和 GF109203X 抑制 PKC 途径可抑制 TNFα 诱导的 ICAM-1 表达。总之，我们表明 ATGL 敲低通过激活 NFκB 和 PKC 增加 TNFα 诱导的 ICAM-1 表达，从而增加单核细胞与内皮细胞的黏附。这些结果表明，ATGL 表达减少可能会影响中性脂肪贮积病和胰岛素抵抗状态中的动脉粥样硬化过程。
