Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Department of Endocrinology and Metabolism, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Biochem Biophys Res Commun. 2020 May 14;525(4):1095-1102. doi: 10.1016/j.bbrc.2020.03.040. Epub 2020 Mar 14.
Cell adhesion molecule L1-like protein (CHL1) is a member of neural recognition molecules of immunoglobulin superfamily primarily expressing in the nervous system. CHL1 regulates neuronal migration, axonal growth, and dendritic projection. Downregulation of CHL1 has been reported in β cells of patients with type 2 diabetes (T2DM). However, the detailed role of CHL1 in β cells has not been characterized. In this study, Real-Time PCR and Western blot were applied to investigate the tissue/cell distribution and expression of CHL1. Gain- or loss-of function studies were conducted in MIN6 cells to determine the effects of CHL1 on cell proliferation, apoptosis, cell cycle, and insulin secretion. Following silencing of CHL1 in MIN6 cells (si-CHL1), insulin secretion and the number of insulin secretary granules <50 nm from the cell membrane decreased in response to 20 mM glucose. Besides, silencing of CHL1 induced cell proliferation, reduced apoptosis, and prolonged S phase and shortened G1 phase of the cell cycle, contrary to overexpressing of CHL1. The inhibitor of ERK1/2MAPK eliminated the effect of CHL1 deficiency on the proliferation of MIN6 cells. In addition, high-fat diet could result in increased islet volume and β cell proliferation, decreased CHL1 expression and activation of ERK pathway in mice islets. Consequently, CHL1 expression was decreased in islets of high-fat induced mice, which resulted in cell proliferation via ERK pathway and regulation of the cell cycle through p53 pathway. These mechanisms may contribute to pancreatic β cell compensatory hyperplasia in obesity-induced pre-diabetes.
细胞黏附分子 L1 样蛋白 (CHL1) 是免疫球蛋白超家族的神经识别分子成员，主要在神经系统中表达。CHL1 调节神经元迁移、轴突生长和树突投射。已有研究报道 2 型糖尿病 (T2DM) 患者的β细胞中 CHL1 表达下调。然而，CHL1 在β细胞中的详细作用尚未得到阐明。本研究应用实时 PCR 和 Western blot 分析 CHL1 的组织/细胞分布和表达。在 MIN6 细胞中进行增益或失能研究，以确定 CHL1 对细胞增殖、凋亡、细胞周期和胰岛素分泌的影响。在 MIN6 细胞中沉默 CHL1（si-CHL1）后，对 20mM 葡萄糖的反应中，胰岛素分泌和距离细胞膜 <50nm 的胰岛素分泌颗粒数量减少。此外，沉默 CHL1 诱导细胞增殖，减少凋亡，并延长细胞周期的 S 期和缩短 G1 期，与过表达 CHL1 相反。ERK1/2MAPK 的抑制剂消除了 CHL1 缺乏对 MIN6 细胞增殖的影响。此外，高脂肪饮食可导致胰岛体积增加和β细胞增殖，降低小鼠胰岛中 CHL1 的表达和 ERK 通路的激活。因此，高脂肪诱导的小鼠胰岛中 CHL1 的表达减少，通过 ERK 通路导致细胞增殖，并通过 p53 通路调节细胞周期。这些机制可能有助于肥胖诱导的糖尿病前期中胰腺β细胞的代偿性增生。
