Sun Yifei, Zhang Yihan, Zhang Jifeng, Chen Y Eugene, Jin Jian-Ping, Zhang Kezhong, Mou Hongmei, Liang Xiubin, Xu Jie
Center for Advanced Models for Translational Sciences and Therapeutics, University of Michigan Medical Center, University of Michigan Medical School, Ann Arbor, MI, United States.
The Mucosal Immunology & Biology Research Center, Massachusetts General Hospital, 55 Fruit Street, Jackson 1402, Boston, MA 02114, USA.
Res Sq. 2023 Jul 21:rs.3.rs-3112506. doi: 10.21203/rs.3.rs-3112506/v1.
sodium-dependent glucose cotransporter 1 and 2 (SGLT1/2) belong to the family of glucose transporters, encoded by SLC5A1 and SLC5A2, respectively. SGLT-2 is almost exclusively expressed in the renal proximal convoluted tubule cells. SGLT-1 is expressed in the kidneys but also in other organs throughout the body. Many SGLT inhibitor drugs have been developed based on the mechanism of blocking glucose (re)absorption mediated by SGLT1/2, and several have gained major regulatory agencies' approval for treating diabetes. Intriguingly these drugs are also effective in treating diseases beyond diabetes, for example heart failure and chronic kidney disease. We recently discovered that SGLT-1 is upregulated in the airway epithelial cells derived from patients of cystic fibrosis (CF), a devastating genetic disease affecting greater than 70,000 worldwide.
in the present work, we show that the SGLT-1 upregulation is coupled with elevated endoplasmic reticulum (ER) stress response, indicated by activation of the primary ER stress senor inositol-requiring protein 1a (IRE1a) and the ER stress-induced transcription factor X-box binding protein 1 (XBP1), in CF epithelial cells, and in epithelial cells of other stress conditions. Through biochemistry experiments, we demonstrated that XBP1 acts as a transcription factor for SLC5A1 by directly binding to its promoter region. Targeting this ER stress → SLC5A1 axis by either the ER stress inhibitor Rapamycin or the SGLT-1 inhibitor Sotagliflozin was effective in attenuating the ER stress response and reducing the SGLT-1 levels in these cellular model systems.
the present work establishes a causal relationship between ER stress and SGLT-1 upregulation and provides a mechanistic explanation why SGLT inhibitor drugs benefit diseases beyond diabetes.
钠依赖性葡萄糖共转运蛋白1和2（SGLT1/2）属于葡萄糖转运蛋白家族，分别由SLC5A1和SLC5A2编码。SGLT-2几乎只在肾近端曲管细胞中表达。SGLT-1在肾脏中表达，但也在全身其他器官中表达。基于阻断SGLT1/2介导的葡萄糖（再）吸收机制，已经开发了许多SGLT抑制剂药物，其中几种已获得主要监管机构批准用于治疗糖尿病。有趣的是，这些药物在治疗糖尿病以外的疾病方面也有效，例如心力衰竭和慢性肾病。我们最近发现，在囊性纤维化（CF）患者来源的气道上皮细胞中，SGLT-1上调，CF是一种毁灭性的遗传疾病，全球有超过70000人受其影响。
在本研究中，我们表明，在CF上皮细胞以及其他应激条件下的上皮细胞中，SGLT-1上调与内质网（ER）应激反应增强相关，这表现为内质网应激主要传感器肌醇需要蛋白1α（IRE1α）和内质网应激诱导转录因子X盒结合蛋白1（XBP1）的激活。通过生化实验，我们证明XBP1通过直接结合其启动子区域作为SLC5A1的转录因子。在这些细胞模型系统中，通过内质网应激抑制剂雷帕霉素或SGLT-1抑制剂索格列净靶向该内质网应激→SLC5A1轴，可有效减轻内质网应激反应并降低SGLT-1水平。
本研究建立了内质网应激与SGLT-1上调之间的因果关系，并为SGLT抑制剂药物为何对糖尿病以外的疾病有益提供了机制解释。
