Li Hong, Lin Lin, Huang Xiaoheng, Lu Yang, Su Xiong
School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
School of Life Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China; Suzhou Key Laboratory of Systems Biomedicine, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, China.
J Biol Chem. 2024 Dec;300(12):107912. doi: 10.1016/j.jbc.2024.107912. Epub 2024 Oct 21.
Glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is metabolically regulated and progressively diminished during the development of type 2 diabetes (T2D). This dynamic process is tightly coupled with fatty acid metabolism, but the underlying mechanisms remain poorly understood. Fatty acid 2-hydroxylase (FA2H) catalyzes the conversion of fatty acids to chiral specific (R)-2-hydroxy fatty acids ((R)-2-OHFAs), which influences cell metabolism. However, little is known about its potential coupling with GSIS in pancreatic β cells. Here, we showed that Fa2h knockout decreases plasma membrane localization and protein level of glucose transporter 2 (GLUT2), which is essential for GSIS, thereby controlling blood glucose homeostasis. Conversely, FA2H overexpression increases GLUT2 on the plasma membrane and enhances GSIS. Mechanistically, FA2H suppresses the internalization and trafficking of GLUT2 to the lysosomes for degradation. Overexpression of wild-type FA2H, but not its mutant with impaired hydroxylase activity in the pancreatic β-cells, improves glucose tolerance by promoting insulin secretion. Levels of 2-OHFAs and Fa2h gene expression are lower in high-fat diet-induced obese mouse islets with impaired GSIS. Moreover, lower gene expression of FA2H is observed in a set of human T2D islets when the insulin secretion index is significantly suppressed, indicating the potential involvement of FA2H in regulating mouse and human GSIS. Collectively, our results identified an FA chemical switch to maintain the proper response of GSIS in pancreatic β cells and provided a new perspective on the β-cell failure that triggers T2D.
胰腺β细胞中的葡萄糖刺激胰岛素分泌（GSIS）受到代谢调节，并且在2型糖尿病（T2D）发展过程中逐渐减弱。这一动态过程与脂肪酸代谢紧密相关，但其潜在机制仍知之甚少。脂肪酸2-羟化酶（FA2H）催化脂肪酸转化为手性特异性（R）-2-羟基脂肪酸（（R）-2-OHFAs），这会影响细胞代谢。然而，其在胰腺β细胞中与GSIS潜在偶联的情况却鲜为人知。在此，我们表明Fa2h基因敲除会降低对GSIS至关重要的葡萄糖转运蛋白2（GLUT2）的质膜定位和蛋白水平，从而控制血糖稳态。相反，FA2H过表达会增加质膜上的GLUT2并增强GSIS。从机制上讲，FA2H抑制GLUT2内化并转运至溶酶体进行降解。在胰腺β细胞中过表达野生型FA2H，而非具有受损羟化酶活性的突变体，可通过促进胰岛素分泌改善葡萄糖耐量。在GSIS受损的高脂饮食诱导的肥胖小鼠胰岛中，2-OHFAs水平和Fa2h基因表达较低。此外，在一组人类T2D胰岛中，当胰岛素分泌指数显著受抑时，观察到FA2H基因表达较低，这表明FA2H可能参与调节小鼠和人类的GSIS。总体而言，我们的结果确定了一种FA化学开关，以维持胰腺β细胞中GSIS的适当反应，并为引发T2D的β细胞功能衰竭提供了新视角。
