Cao Ting, Yang Dan, Zhang Xiong, Wang Yueqian, Qiao Zhengdong, Gao Lili, Liang Yongjun, Yu Bo, Zhang Peng
Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Pudong, Shanghai, 201399, China.
Department of Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, China.
Cell Biol Toxicol. 2017 Oct;33(5):457-466. doi: 10.1007/s10565-017-9387-8. Epub 2017 Feb 28.
Dysregulated glucagon secretion is a hallmark of type 2 diabetes (T2D). To date, few effective therapeutic agents target on deranged glucagon secretion. Family with sequence similarity 3 member D (FAM3D) is a novel gut-derived cytokine-like protein, and its secretion timing is contrary to that of glucagon. However, the roles of FAM3D in metabolic disorder and its biological functions are largely unknown. In the present study, we investigated whether FAM3D modulates glucagon production in mouse pancreatic alpha TC1 clone 6 (αTC1-6) cells. Glucagon secretion, prohormone convertase 2 (PC2) activity, and mitogen-activated protein kinase (MAPK) pathway were assessed. Exogenous FAM3D inhibited glucagon secretion, PC2 activity, as well as extracellular-regulated protein kinase 1/2 (ERK1/2) signaling and induced MAPK phosphatase 1 (MKP1) expression. Moreover, knockdown of MKP1 and inhibition of ERK1/2 abolished and potentiated the inhibitory effect of FAM3D on glucagon secretion, respectively. Taken together, FAM3D inhibits glucagon secretion via MKP1-dependent suppression of ERK1/2 signaling. These results provide rationale for developing the therapeutic potential of FAM3D for dysregulated glucagon secretion and T2D.
胰高血糖素分泌失调是2型糖尿病（T2D）的一个标志。迄今为止，很少有有效的治疗药物针对紊乱的胰高血糖素分泌。序列相似性家族3成员D（FAM3D）是一种新型的肠道来源的细胞因子样蛋白，其分泌时间与胰高血糖素相反。然而，FAM3D在代谢紊乱中的作用及其生物学功能在很大程度上尚不清楚。在本研究中，我们调查了FAM3D是否调节小鼠胰腺αTC1克隆6（αTC1-6）细胞中胰高血糖素的产生。评估了胰高血糖素分泌、激素原转化酶2（PC2）活性和丝裂原活化蛋白激酶（MAPK）途径。外源性FAM3D抑制胰高血糖素分泌、PC2活性以及细胞外调节蛋白激酶1/2（ERK1/2）信号传导，并诱导丝裂原活化蛋白激酶磷酸酶1（MKP1）表达。此外，MKP1的敲低和ERK1/2的抑制分别消除和增强了FAM3D对胰高血糖素分泌的抑制作用。综上所述，FAM3D通过依赖MKP1的ERK1/2信号抑制来抑制胰高血糖素分泌。这些结果为开发FAM3D对失调的胰高血糖素分泌和T2D的治疗潜力提供了理论依据。
