Sema4D 缺乏通过维持肝细胞内 GLUT2 来增强葡萄糖耐量。
Sema4D deficiency enhances glucose tolerance through GLUT2 retention in hepatocytes.
机构信息
Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, 32 West Second Section, First Ring Road, Chengdu, 610072, China.
Clinical Immunology Translational Medicine Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, 610072, China.
出版信息
J Transl Med. 2024 Sep 27;22(1):864. doi: 10.1186/s12967-024-05694-7.
BACKGROUND
The glucose transporter 2 (GLUT2) is constitutively expressed in pancreatic beta cells and hepatocytes of mice. It is the most important receptor in glucose-stimulated insulin release and hepatic glucose transport. The Sema4D is a signalin receptor on cell membranes. The correlation between Sema4D and GLUT2 has not been reported previously. We investigated whether knockdown of Sema4D could exert a hypoglycemic effect based on the increased GLUT2 expression in Sema4D -/- mice hepatocytes.
METHODS
The glucose tolerance test and insulin tolerance test in sema4D -/- and sema4D +/+ mice were compared before and after streptozotocin (STZ) injection; the expression of GLUT2 content on the membrane surface of both groups was verified by Western blot. Then, the levels of insulin and C-peptide in the serum of the two groups of mice after STZ injection were measured by ELISA; the differentially expressed mRNAs in the liver of the two groups of mice were analyzed by transcriptomic analysis; then the differences in the expression of GLUT2, glycogen, insulin and glucagon in the two groups of mice were compared by tissue section staining. Finally, metabolomics analysis was performed to analyze the metabolites differentially expressed in the two groups of mice.
KEY FINDINGS
First, Sema4D -/- male mice exhibited significantly greater glucose tolerance than wild-type mice in a hyperglycemic environment. Secondly, Sema4D -/- mice had more retained GLUT2 in liver membranes after STZ injection according to an immunofluorescence assay. After STZ injection, Sema4D -/- male mice did not exhibit fasting hyperinsulinemia like wild-type mice. Finally, analysis of metabolomic and immunohistochemical data also revealed that Sema4D -/- mice produce hypoglycemic effects by enhancing the pentose phosphate pathway, but not glycogen synthesis.
CONCLUSIONS
Thus, Sema4D may play an important role in the regulation of glucose homeostasis by affecting GLUT2 synthesis.
背景
葡萄糖转运蛋白 2（GLUT2）在小鼠的胰腺β细胞和肝细胞中持续表达。它是葡萄糖刺激胰岛素释放和肝葡萄糖转运的最重要受体。Sema4D 是细胞膜上的信号受体。以前没有报道过 Sema4D 与 GLUT2 之间的相关性。我们研究了 Sema4D 敲低是否可以基于 Sema4D-/- 小鼠肝细胞中 GLUT2 表达的增加发挥降血糖作用。
方法
比较了链脲佐菌素（STZ）注射前后 Sema4D-/-和 Sema4D+/+小鼠的葡萄糖耐量试验和胰岛素耐量试验；通过 Western blot 验证了两组细胞膜表面 GLUT2 含量的表达。然后，通过 ELISA 测量两组小鼠 STZ 注射后血清中的胰岛素和 C 肽水平；通过转录组分析分析两组小鼠肝脏中差异表达的 mRNA；然后通过组织切片染色比较两组小鼠 GLUT2、糖原、胰岛素和胰高血糖素的表达差异。最后，进行代谢组学分析以分析两组小鼠中差异表达的代谢物。
主要发现
首先，在高血糖环境中，Sema4D-/-雄性小鼠的葡萄糖耐量明显优于野生型小鼠。其次，根据免疫荧光测定，STZ 注射后 Sema4D-/-小鼠的肝细胞膜中保留了更多的 GLUT2。STZ 注射后，Sema4D-/-雄性小鼠不像野生型小鼠那样出现空腹高胰岛素血症。最后，代谢组学和免疫组织化学数据分析还表明，Sema4D-/-小鼠通过增强戊糖磷酸途径而不是糖原合成产生降血糖作用。
结论
因此，Sema4D 可能通过影响 GLUT2 合成在调节葡萄糖稳态中发挥重要作用。
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