Mukhuty Alpana, Fouzder Chandrani, Mukherjee Sandip, Malick Chandan, Mukhopadhyay Satinath, Bhattacharya Samir, Kundu Rakesh
Cell Signaling Laboratory, Centre of Advanced Studies, Department of Zoology, Visva-Bharati University, Santiniketan 731 235, India.
Cellular and Molecular Endocrinology Laboratory, Centre of Advanced Studies, Department of Zoology, Visva-Bharati University, Santiniketan 731 235, India.
Biochem Biophys Res Commun. 2017 Sep 30;491(4):1118-1124. doi: 10.1016/j.bbrc.2017.08.022. Epub 2017 Aug 7.
Islets of type 2 diabetes patients display inflammation, elevated levels of cytokines and macrophages. The master regulator of inflammation in the islets is free fatty acids (FFA). It has already been reported that FFA and TLR4 stimulation induces pro-inflammatory factors in the islets. In this report we demonstrate that excess lipid triggers Fetuin-A (FetA) secretion from the pancreatic β-cells. Palmitate treatment to MIN6 cells showed significantly elevated FetA levels in respect to their controls. Fatty acid induces the FetA gene and protein expression in the pancreatic β-cells via TLR4 and over-expression of NF-κB. In the NF-κB knocked down MIN6 cells palmitate could not trigger FetA release into the incubation medium. These results suggest that NF-κB mediates palmitate stimulated FetA secretion from the pancreatic β-cells. Blocking the activity of TLR4 by CLI-095 incubation or TLR4 siRNA restored insulin secretion which confirmed the role of TLR4 in FFA-FetA mediated pancreatic β-cell dysfunction. Palmitate mediated expression of NF-κB enahnced inflammatory response through expression of cytokines such as IL-1β and IL-6. These results suggest that FFA mediated FetA secretion from pancreatic β-cells lead to their dysfunction via FFA-TLR4 pathway. FetA thus creates an inflammatory environment in the pancreatic islets that can become a possible cause behind pancreatic β-cell dysfunction in chronic hyperlipidemic condition.
2型糖尿病患者的胰岛表现出炎症、细胞因子和巨噬细胞水平升高。胰岛炎症的主要调节因子是游离脂肪酸（FFA）。已有报道称，FFA和Toll样受体4（TLR4）刺激可诱导胰岛中的促炎因子。在本报告中，我们证明过量脂质会触发胰腺β细胞分泌胎球蛋白A（FetA）。用棕榈酸处理MIN6细胞后，与对照组相比，FetA水平显著升高。脂肪酸通过TLR4和核因子κB（NF-κB）的过表达诱导胰腺β细胞中FetA基因和蛋白的表达。在NF-κB基因敲低的MIN6细胞中，棕榈酸不能触发FetA释放到培养液中。这些结果表明，NF-κB介导棕榈酸刺激胰腺β细胞分泌FetA。通过CLI-095孵育或TLR4小干扰RNA（siRNA）阻断TLR4的活性可恢复胰岛素分泌，这证实了TLR4在FFA-FetA介导的胰腺β细胞功能障碍中的作用。棕榈酸介导的NF-κB表达通过白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）等细胞因子的表达增强了炎症反应。这些结果表明，FFA介导的胰腺β细胞分泌FetA通过FFA-TLR4途径导致其功能障碍。因此，FetA在胰岛中营造了一种炎症环境，这可能是慢性高脂血症状态下胰腺β细胞功能障碍的一个潜在原因。
