Vitamin D Up-regulates Glucose Transporter 4 (GLUT4) Translocation and Glucose Utilization Mediated by Cystathionine-γ-lyase (CSE) Activation and H2S Formation in 3T3L1 Adipocytes
Vitamin D Up-regulates Glucose Transporter 4 (GLUT4) Translocation and Glucose Utilization Mediated by Cystathionine-γ-lyase (CSE) Activation and H2S Formation in 3T3L1 Adipocytes
复制标题
DOI：
10.1074/jbc.m112.407833
复制
发表时间：
2012-12-07
影响因子：
4.8
通讯作者：
Jain, Sushil K.
中科院分区：
文献类型：
--
作者：
Manna, Prasenjit;Jain, Sushil K.
对于维生素D补充剂在降低糖尿病患者血糖中的有益作用的科学解释仍有待确定。本研究探讨了维生素D补充剂调节糖尿病患者葡萄糖代谢的生化机制。在存在或不存在维生素D的活性形式1，25-二羟基维生素D-3（1，25（OH）（2）D-3）（25，50 nM）的情况下，用高葡萄糖（HG，25 mM）处理3 T3 L1脂肪细胞。1，25（OH）（2）D-3处理可显著上调葡萄糖转运蛋白4（GLUT 4）总蛋白的表达及其向细胞表面的转运，并增加葡萄糖的摄取和利用。1，25（OH）（2）D-3还引起HG处理的脂肪细胞中胱硫醚-γ-裂解酶（CSE）活化和H2S形成。炔丙基甘氨酸（一种催化H2S形成的CSE抑制剂）可阻止1，25（OH）（2）D-3对GLUT 4易位、葡萄糖利用和H2S形成的影响。使用反义CSE的研究还证明，与对照相比，在补充1，25（OH）（2）D-3的CSE-siRNA转染的脂肪细胞中，GLUT 4易位以及葡萄糖摄取和利用受到抑制。在HG处理的脂肪细胞中，与单独使用胰岛素或1，25（OH）（2）D-3相比，1，25（OH）（2）D-3处理沿着胰岛素增强了GLUT 4转运和葡萄糖利用。1，25（OH）（2）D-3补充还抑制了HG处理的脂肪细胞中单核细胞趋化蛋白-1并刺激脂联素分泌，并且在炔丙基甘氨酸处理或CSE敲除的脂肪细胞中阻止了这种积极作用。这是第一份证明1，25（OH）（2）D-3上调GLUT 4易位和葡萄糖利用并减少炎症标志物的报告，这是由脂肪细胞中CSE活化和H2S形成介导的。这项研究为1，25（OH）（2）D-3上调维持葡萄糖代谢所必需的GLUT 4易位的新分子机制提供了证据。
A scientific explanation for the beneficial role of vitamin D supplementation in the lowering of glycemia in diabetes remains to be determined. This study examined the biochemical mechanism by which vitamin D supplementation regulates glucose metabolism in diabetes. 3T3L1 adipocytes were treated with high glucose (HG, 25 mM) in the presence or absence of 1,25-dihydroxyvitamin D-3(1,25(OH)(2)D-3) (25, 50 nM), the active form of vitamin D. 1,25(OH)(2)D-3 treatment caused significant up-regulation of GLUT4 total protein expression and its trans-location to cell surface, and an increase in glucose uptake as well as glucose utilization in HG-treated cells. 1,25(OH)(2)D-3 also caused cystathionine-gamma-lyase (CSE) activation and H2S formation in HG-treated adipocytes. The effect of 1,25(OH)(2)D-3 on GLUT4 translocation, glucose utilization, and H2S formation was prevented by propargylglycine, an inhibitor of CSE that catalyzes H2S formation. Studies using antisense CSE also demonstrated the inhibition of GLUT4 translocation as well as glucose uptake and utilization in 1,25(OH)(2)D-3-supplemented CSE-siRNA-transfected adipocytes compared with controls. 1,25(OH)(2)D-3 treatment along with insulin enhanced GLUT4 translocation and glucose utilization compared with either insulin or 1,25(OH)(2)D-3 alone in HG-treated adipocytes. 1,25(OH)(2)D-3 supplementation also inhibited monocyte chemoattractant protein-1 and stimulated adiponectin secretion in HG-treated adipocytes, and this positive effect was prevented in propargylglycine-treated or CSE-knockdown adipocytes. This is the first report to demonstrate that 1,25(OH)(2)D-3 up-regulates GLUT4 translocation and glucose utilization and decreases inflammatory markers, which is mediated by CSE activation and H2S formation in adipocytes. This study provides evidence for a novel molecular mechanism by which 1,25(OH)(2)D-3 can up-regulate the GLUT4 translocation essential for maintenance of glucose metabolism.