Xia Fangzhen, Zhang Ziteng, Qian Zhen, Fang Xiaoyu, Wang Junxue, Wang Yan, Sun Guoting, Yu Yuefeng, Wang Ninjian, Zhen Junke, Liu Yan, Lu Yingli
Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
Mol Metab. 2025 Jan;91:102069. doi: 10.1016/j.molmet.2024.102069. Epub 2024 Nov 19.
B7-H4 (B7S1, B7x, VTCN1) is an important immune checkpoint molecule that maintains immune homeostasis and is also expressed in pancreatic β cells. The polymorphism of B7-H4 influences the prevalence of Type 2 diabetes (T2D), suggesting a potential role of B7-H4 in the physiological function of pancreatic β cells and the pathogenesis of T2D.
β-cell-specific B7-H4 knockout mice (B7-H4 cKO mice) and their wild-type littermates were used to investigate the in vivo effects of B7-H4 on pancreatic β-cell morphology and function. AAV2/8-ins2-B7H4 and a control virus were infused via the pancreatic intraduct into high-fat diet (HFD)-treated mice to elucidate the therapeutic effect of B7-H4. RNA sequencing was conducted on primary islets. A Luminex assay was used to quantify cytokine changes in B7-H4 cKO mice. Electron microscopy imaging was used to observe insulin secretory vesicles in pancreatic β cells.
Lesion of B7-H4 in β cells results in glucose intolerance due to reduced β-cell mass and deficient insulin secretion, whereas overexpression of B7-H4 in β cells ameliorates glucose intolerance in HFD-fed mice. Mechanistically, B7-H4 deficiency activates signal transducer and activator of transcription 5 (Stat5) signalling, which inhibits the expression of apolipoprotein F (Apof), leading to reduced cholesterol efflux and accumulated cholesterol in β cells, thereby impairing insulin processing and secretion. Overexpression of Apof in β cells or intraperitoneal injection of a Stat5 inhibitor reverses the metabolic phenotype and insulin secretion deficiency in B7-H4 cKO mice.
Our study demonstrated that B7-H4 plays an important role in regulating β-cell mass and insulin secretion, which may shed new light on the development of novel strategies for T2D treatment.
B7-H4（B7S1、B7x、VTCN1）是一种重要的免疫检查点分子，可维持免疫稳态，并且也在胰腺β细胞中表达。B7-H4的多态性影响2型糖尿病（T2D）的患病率，提示B7-H4在胰腺β细胞的生理功能及T2D发病机制中具有潜在作用。
利用β细胞特异性B7-H4基因敲除小鼠（B7-H4 cKO小鼠）及其野生型同窝小鼠，研究B7-H4对胰腺β细胞形态和功能的体内作用。将AAV2/8-ins2-B7H4和对照病毒经胰管注入高脂饮食（HFD）处理的小鼠体内，以阐明B7-H4的治疗作用。对原代胰岛进行RNA测序。采用Luminex检测法对B7-H4 cKO小鼠体内细胞因子变化进行定量分析。利用电子显微镜成像观察胰腺β细胞中的胰岛素分泌囊泡。
β细胞中B7-H4缺失导致葡萄糖不耐受，原因是β细胞数量减少和胰岛素分泌不足，而β细胞中B7-H4过表达可改善HFD喂养小鼠的葡萄糖不耐受。机制上，B7-H4缺陷激活信号转导及转录激活因子5（Stat5）信号通路，抑制载脂蛋白F（Apof）表达，导致β细胞内胆固醇流出减少、胆固醇蓄积，从而损害胰岛素加工和分泌。β细胞中Apof过表达或腹腔注射Stat5抑制剂可逆转B7-H4 cKO小鼠的代谢表型和胰岛素分泌缺陷。
我们的研究表明，B7-H4在调节β细胞数量和胰岛素分泌中起重要作用，这可能为T2D治疗新策略的开发提供新线索。
