Role of the carboxylate transporter SLC16A13 in energy and glucose homeostasis

2型糖尿病（T2D）是世界范围内日益流行的健康威胁。糖尿病相关的死亡率比非糖尿病患者高2-3倍。更好地了解致病因素和更有效的治疗是必不可少的临床要求。SLC16A13基因编码一种膜结合的单羧酸转运蛋白，在2项独立的患者全基因组关联研究中显示，SLC16A13基因与T2D的发生密切相关（Hara K等，Hum Mol Genet）。， 2014; Sigma Consortium et al., Nature 2014)。该基因在T2D发展中的功能和作用尚不清楚。通过人SLC16A13过表达HEK293细胞，我们首次确定了该转运体的底物。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HEK293细胞中表达的增加导致新生脂肪生成的增加。这些数据支持了SLC16A13与非酒精性脂肪性肝病和胰岛素抵抗的发展相关的观点。根据这些数据，我们使用CRISPR/Cas9产生的SLC16A13基因敲除小鼠免受饮食性肥胖和NAFLD的影响。因此，我们假设SLC16A13通过影响作为各种肝脏通量底物的单羧酸盐的运输，促进了肥胖、非酒精性脂肪性肝病和胰岛素抵抗的发展。根据我们的建议，SLC16A13转运体的底物和动力学将通过SLC16A13过表达HEK293细胞的体外和外排实验来详细确定。此外，我们的SLC16A13基因敲除小鼠将首次在体内进行表征，以确定其对胰岛素抵抗和T2D的影响。最后，我们将检测t2dm患者和非t2dm患者肝脏和脂肪组织中SLC16A13的表达。我们的数据将提供关于候选基因SLC16A13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性肝病、T2D和肥胖的新治疗策略。

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.