Nag Snehasish, Mandal Samanwita, Majumdar Tanmay, Mukhopadhyay Satinath, Kundu Rakesh
Cell Signaling Laboratory, Department of Zoology, Visva-Bharati University, Santiniketan, 731235, India.
National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi, 110067, India.
Biochem Biophys Res Commun. 2023 Mar 5;647:55-61. doi: 10.1016/j.bbrc.2023.01.070. Epub 2023 Jan 23.
Dipeptidyl peptidase 4 (DPP-IV) is a ubiquitous proteolytic enzyme that cleaves incretin hormones, such as glucagon-like peptide 1 (GLP1) and gastric inhibitory protein (GIP), leading to reduced glucose stimulated insulin secretion from the pancreatic beta cells. The functionally active enzyme is present in a membrane bound form in several cell types as well as in a soluble form in the circulation. The present report deals with DPP-IV expression and its regulation in the pancreatic beta cells in presence of free fatty acids (FFAs) and Fetuin-A, a circulatory glycoprotein associated with insulin resistance in humans and animals. FFA and Fetuin-A individually or in combination trigger DPP-IV expression in MIN6 cells. Islets isolated from high fat diet fed (HFD) mice (16 weeks) showed higher levels of DPP-IV expression than standard diet (SD) fed mice. Fetuin-A increased DPP-IV expression in HFD mice (4 weeks). Inhibition of TLR4 or NFkB prevented palmitate-Fetuin-A mediated DPP-IV expression in MIN6. It has been seen that Fetuin-A alone also could trigger DPP-IV expression in MIN6 cells via NFkB. Additionally, palmitate treatment exhibited reduced level of soluble DPP-IV in the media of MIN6 culture, which corroborated with the expression pattern of its protease, KLK5 that cleaves and releases the membrane bound DPP-IV into the secretion. Our results demonstrate that FFA-Fetuin-A upregulates DPP-IV expression in the pancreatic beta cells through the TLR4-NFkB pathway.
二肽基肽酶4（DPP-IV）是一种普遍存在的蛋白水解酶，可切割肠促胰岛素激素，如胰高血糖素样肽1（GLP1）和胃抑制蛋白（GIP），导致胰腺β细胞中葡萄糖刺激的胰岛素分泌减少。功能活性酶以膜结合形式存在于多种细胞类型中，也以可溶性形式存在于循环中。本报告探讨了在游离脂肪酸（FFA）和胎球蛋白A（一种与人和动物胰岛素抵抗相关的循环糖蛋白）存在的情况下，DPP-IV在胰腺β细胞中的表达及其调控。FFA和胎球蛋白A单独或联合触发MIN6细胞中DPP-IV的表达。从高脂饮食喂养（HFD）16周的小鼠分离的胰岛显示出比标准饮食（SD）喂养的小鼠更高水平的DPP-IV表达。胎球蛋白A增加了HFD小鼠（4周）中DPP-IV的表达。抑制TLR4或NFkB可阻止棕榈酸-胎球蛋白A介导的MIN6中DPP-IV的表达。已经发现，单独的胎球蛋白A也可以通过NFkB触发MIN6细胞中DPP-IV的表达。此外，棕榈酸处理显示MIN6培养物培养基中可溶性DPP-IV水平降低，这与其蛋白酶KLK5的表达模式一致，KLK5可切割并将膜结合的DPP-IV释放到分泌物中。我们的结果表明，FFA-胎球蛋白A通过TLR4-NFkB途径上调胰腺β细胞中DPP-IV的表达。
