FAM3A调控胰岛β细胞胰岛素分泌过程的机制

FAM3A is a member of FAM3 (Family with sequence similarity 3) cytokine-like gene family which consists of four members designated as FAM3A, FAM3B(PANDER), FAM3C and FAM3D, respectively. In the past decade, my research had been focused on demonstrating the role of FAM3B, also called PANDER, in regulation of glucose and lipid metabolism. So far, the biological function of FAM3A remains largely unknown. We had recently demonstrated that FAM3A is a novel target gene of PPARγ, and it exerts significant inhibitory effects on hepatic glucose production and lipid synthesis via enhancement of ATP production and release. Our preliminary research had also revealed that FAM3A is specifically expressed in islet within human and rodent pancreas, and its expression is markedly reduced in type 2 diabetic condition. We also found that FAM3A protein is mainly located in the mitochondria，but not in the cytoplasma and nucleus of pancreatic beta cells. The current study aims to study the potential role and mechanism of FAM3A in the regulation of insulin secretion in pancreatic islet beta cells. Aim 1: in vivo analysis of insulin secretion of FAM3A-deficient mice or type 2 diabetic mice in response to glucose or other secretagogues; Aim 2: to determine the subcellular location of FAM3A protein in the mitochondria, and whether it modulates ATP production and release in pancreatic beta cells; Aim 3: to determine whether FAM3A regulates insulin secretion via ATP-mediated impact on the ATP-sensitive K+ channel and P2 receptor (Purigenic receptor for ATP) signaling pathway. Significance: demonstration of the role and mechanism of FAM3A in the regulation of insulin secretion in pancreatic beta cells will shed light on the mechanisms of islet dysfunction and type 2 diabetes. FAM3A might be a novel therapeutic target for islet dysfunction and type 2 diabetes.

FAM3家族是2002年发现的细胞因子样基因家族，包括FAM3A，FAM3B/PANDER、FAM3C和FAM3D四个成员。申请人长期研究PANDER在糖脂代谢中的调控机制。目前，FAM3A的生物学功能尚不清楚。申请人最近阐明FAM3A是PPARγ的靶基因，其通过影响ATP合成分泌在肝脏糖脂代谢中起重要调控作用。预实验揭示在人与动物胰腺中，FAM3A特异表达于胰岛β细胞中，且在2型糖尿病发生时显著下降。本研究拟在前期发现的基础上，进一步：1）在动物整体水平上分析FAM3A基因敲除小鼠胰岛素分泌功能的变化；2）明确FAM3A蛋白在胰岛β细胞线粒体中的定位及对ATP合成分泌的影响；3）深入研究FAM3A通过影响ATP合成分泌调控胰岛β细胞胰岛素分泌的机制。阐明新线粒体蛋白FAM3A在胰岛素分泌调控中的作用及其机制，对深入了解胰岛β细胞胰岛素分泌障碍的发生过程及2型糖尿病防治具有重要的科学意义。

在前期研究中，课题组揭示FAM3基因家族成员FAM3A是一个新线粒体蛋白，其在抑制肝脏糖异生及脂质合成，及增加脂质氧化过程中起重要作用。肥胖及胰岛素抵抗发生时，肝脏FAM3A表达下调，是肝脏糖异生及脂质合成增加的重要新机制。然而，FAM3A是否在胰岛β细胞功能代谢中起重要调控作用未知。在该自然基金的资助下，申请人课题组阐明：1）FAM3A通过调控ATP合成、抑制ROS生成与调节细胞钙稳态，在胰岛素表达与分泌及胰岛β细胞增殖过程起重要调控作用。FAM3A表达下降，是2型糖尿病发生过程中胰岛β细胞功能障碍（胰岛素分泌障碍及胰岛beta细胞损伤）发生的重要新机制；2）在肥胖及胰岛素抵抗发生过程中，高血糖及游离脂肪酸会激活转录因子NFE2，其诱导miR-423-5p表达。miR-423-5p直接抑制FAM3A表达及其信号通路，从而诱导胰岛β细胞功能障碍及肝脏糖脂代谢异常，最终导致2新糖尿病及脂肪肝发生；3）确立FAM3C通过调控HSF1及CaM表达，以非胰岛素及钙离子依赖的途径激活Akt通路及抑制mTOR通路，抑制肝脏糖异生及脂质合成过程，缓解糖尿病及脂肪肝。以上系列研究揭示了多条新的糖脂代谢调控通路，及数个潜在的糖尿病及脂肪肝干预靶点。这些研究，为深入了解2型糖尿病及脂肪肝的发病机制，注入了新理念及信息。..在课题资助期间，课题组以通讯作者身份发表SCI论文11篇，包括Diabetes （三篇），总影响因子约67。指导6名研究生获得硕士及博士学位。