The immune checkpoint molecule B7-H4 regulates β-cell mass and insulin secretion by modulating cholesterol metabolism through Stat5 signalling

Fangzhen Xia; Ziteng Zhang; Zhen Qian; Xiaoyu Fang; Junxue Wang; Yan Wang; Guoting Sun; Yuefeng Yu; Ninjian Wang; Junke Zhen; Yan Liu; Yingli Lu

doi:10.1016/j.molmet.2024.102069

The immune checkpoint molecule B7-H4 regulates β-cell mass and insulin secretion by modulating cholesterol metabolism through Stat5 signalling

Mol Metab. 2024 Nov 19:102069. doi: 10.1016/j.molmet.2024.102069. Online ahead of print.

Authors

Fangzhen Xia¹, Ziteng Zhang², Zhen Qian³, Xiaoyu Fang³, Junxue Wang², Yan Wang², Guoting Sun², Yuefeng Yu², Ninjian Wang², Junke Zhen⁴, Yan Liu⁵, Yingli Lu⁶

Affiliations

¹ Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China. Electronic address: xiafzh9h@163.com.
² Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China.
³ iHuman Institute, ShanghaiTech University, Shanghai 201210, China.
⁴ Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁵ iHuman Institute, ShanghaiTech University, Shanghai 201210, China. Electronic address: liuyan2@shanghaitech.edu.cn.
⁶ Institute and Department of Endocrinology and Metabolism, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200011, China. Electronic address: luyingli2008@126.com.

PMID: 39571901
DOI: 10.1016/j.molmet.2024.102069

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Apof; B7-H4; Cholesterol metabolism; Insulin secretion; Type 2 diabetes.