Role of the carboxylate transporter SLC16A13 in energy and glucose homeostasis

羧酸转运蛋白 SLC16A13 在能量和葡萄糖稳态中的作用

• 批准号: 416575519
• 负责人: Professor Dr. Andreas L. Birkenfeld
• 金额: --
• 依托单位: Innere Medizin IV: Endokrinologie und Diabetologie, Angiologie, Nephrologie und Klinische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/416575519?language=en
• 关键词: Role; carboxylate; transporter; SLC16A13; energy

Type 2 diabetes (T2D) is an epidemically growing health threat all over the world. Diabetes associated mortality is 2-3 times higher compared to non-affected individuals. A better understanding of pathogenic factors and more efficient therapies are essential clinical requirements. The SLC16A13 gene, which encodes a membrane-bound monocarboxylate transport protein, shows a strong association with the development of T2D in 2 independent genome-wide association studies in patients (Hara K, et al., Hum Mol Genet., 2014, Sigma Consortium et al., Nature 2014). The function and role of the gene in the development of T2D is unknown. By means of human SLC16A13 overexpressing HEK293 cells, we were able to determine a substrate of the transporter for the first time. Furthermore, we can demonstrate that the expression of the gene in the mouse liver increases strongly in food-associated obesity, and that the increased expression in HEK293 cells leads to increased de novo lipogenesis. These data support the idea that SLC16A13 is associated with the development of non-alcoholic fatty liver disease and insulin resistance. In line with these data, in SLC16A13 knockout mice, which we generated using CRISPR/Cas9, are protected from the diet induced obesity and NAFLD. Therefore, we hypothesize that SLC16A13 contributes to the development of obesity, non-alcoholic fatty liver disease, and insulin resistance by affecting the transport of monocarboxylates, which serve as substrates for various hepatic fluxes. With our proposal, the substrates and kinetics of the SLC16A13 transporter will be determined in detail using in vitro in- and efflux experiments in SLC16A13 overexpressing HEK293 cells. In addition, our SLC16A13 knockout mice will be characterized for the first time in vivo to determine the effect on insulin resistance and T2D. Finally, SLC16A13 expression in liver and adipose tissue will be determined in patients with and without T2D. Our data will provide new information on how the candidate gene SLC16A13 leads to type 2 diabetes, NAFLD and obesity, and whether or not the reduction of its function may be a new therapeutic strategy for the treatment of non-alcoholic fatty liver disease, T2D and obesity.

2型糖尿病（T2 D）是世界各地日益严重的健康威胁。糖尿病相关的死亡率比未受影响的个体高2-3倍。更好地了解致病因素和更有效的治疗方法是临床的基本要求。编码膜结合单羧酸转运蛋白的SLC 16 A13基因在患者的2项独立的全基因组关联研究中显示与T2 D的发展强关联（Hara K等人，Mol Genet.，2014年，Sigma Consortium等人，Nature 2014）。该基因在T2 D发展中的功能和作用尚不清楚。通过人SLC 16 A13过表达的HEK 293细胞，我们能够首次确定转运蛋白的底物。此外，我们可以证明该基因在小鼠肝脏中的表达在食物相关性肥胖中强烈增加，并且HEK 293细胞中的表达增加导致从头脂肪生成增加。这些数据支持SLC 16 A13与非酒精性脂肪肝和胰岛素抵抗的发展相关的观点。与这些数据一致，在我们使用CRISPR/Cas9产生的SLC 16 A13敲除小鼠中，保护其免受饮食诱导的肥胖和NAFLD。因此，我们假设SLC 16 A13通过影响单羧酸盐的转运而促进肥胖、非酒精性脂肪肝疾病和胰岛素抵抗的发展，所述单羧酸盐充当各种肝通量的底物。根据我们的提议，将使用SLC 16 A13过表达HEK 293细胞中的体外内排和外排实验详细确定SLC 16 A13转运蛋白的底物和动力学。此外，我们的SLC 16 A13敲除小鼠将首次在体内进行表征，以确定对胰岛素抵抗和T2 D的影响。最后，将在患有和不患有T2 D的患者中确定肝脏和脂肪组织中的SLC 16 A13表达。我们的数据将提供关于候选基因SLC 16 A13如何导致2型糖尿病，NAFLD和肥胖的新信息，以及其功能的降低是否可能成为治疗非酒精性脂肪肝，T2 D和肥胖的新治疗策略。