Lu Zhongyang, Li Yanchun, Jin Junfei, Zhang Xiaoming, Hannun Yusuf A, Huang Yan
Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
Division of Endocrinology, Diabetes and Medical Genetics, Department of Medicine, Medical University of South Carolina, Charleston, SC 29425, USA; Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi 541001, People's Republic of China.
Atherosclerosis. 2015 May;240(1):163-73. doi: 10.1016/j.atherosclerosis.2015.03.013. Epub 2015 Mar 14.
Increased levels of both saturated fatty acids (SFAs) and lipopolysaccharide (LPS) are associated with type 2 diabetes. However, it remains largely unknown how SFAs interact with LPS to regulate inflammatory responses in microvascular endothelial cells (MIC ECs) that are critically involved in atherosclerosis as a diabetic complication. In this study, we compared the effects of LPS, palmitic acid (PA), the most abundant saturated fatty acid, or the combination of LPS and PA on interleukin (IL)-6 expression by MIC ECs and explored the underlying mechanisms.
Human cardiac MIC ECs were treated with LPS, PA and LPS plus PA and the regulatory pathways including receptors, signal transduction, transcription and post-transcription, and sphingolipid metabolism for IL-6 expression were investigated.
G protein-coupled receptor (GPR)40 or free fatty acid receptor 1 (FFA1), but not toll-like receptor 4, was involved in PA-stimulated IL-6 expression. PA not only stimulated IL-6 expression by itself, but also remarkably enhanced LPS-stimulated IL-6 expression via a cooperative stimulation on mitogen-activated protein kinase and nuclear factor kappa B signaling pathways, and both transcriptional and post-transcriptional activation. Furthermore, PA induced a robust neutral sphingomyelinase (nSMase)-mediated sphingomyelin hydrolysis that was involved in PA-augmented IL-6 upregulation.
PA boosted inflammatory response of microvascular endothelial cells to LPS via GPR40 and nSMase.
饱和脂肪酸（SFA）和脂多糖（LPS）水平升高均与2型糖尿病相关。然而，SFA如何与LPS相互作用以调节微血管内皮细胞（MIC ECs）中的炎症反应，在很大程度上仍不清楚，而MIC ECs作为糖尿病并发症动脉粥样硬化的关键参与者。在本研究中，我们比较了LPS、棕榈酸（PA，最丰富的饱和脂肪酸）或LPS与PA的组合对MIC ECs白细胞介素（IL）-6表达的影响，并探讨了潜在机制。
用LPS、PA以及LPS加PA处理人心脏MIC ECs，并研究包括受体、信号转导、转录和转录后以及鞘脂代谢在内的IL-6表达调控途径。
G蛋白偶联受体（GPR）40或游离脂肪酸受体1（FFA1）而非Toll样受体4参与PA刺激的IL-6表达。PA不仅自身刺激IL-6表达，还通过对丝裂原活化蛋白激酶和核因子κB信号通路的协同刺激以及转录和转录后激活，显著增强LPS刺激的IL-6表达。此外，PA诱导了一种由中性鞘磷脂酶（nSMase）介导的强大鞘磷脂水解，这与PA增强的IL-6上调有关。
PA通过GPR40和nSMase增强微血管内皮细胞对LPS的炎症反应。
