Role of the carboxylate transporter SLC16A13 in energy and glucose homeostasis

2型糖尿病(T2D)是世界范围内流行的日益严重的健康威胁。与糖尿病相关的死亡率比未受影响的人高2-3倍。更好地了解致病因素和更有效的治疗是基本的临床要求。SLC16A13基因编码一种膜结合的单羧酸运输蛋白，在两项独立的全基因组相关研究中，SLC16A13基因与T2D的发生密切相关(Hara K等人，Hum Mol Genet，2014，Sigma Consortium等人，《自然》2014)。该基因在T2D发育过程中的功能和作用尚不清楚。通过人SLC16A13高表达HEK293细胞，我们首次能够确定转运蛋白的底物。此外，我们可以证明，在食物相关的肥胖中，该基因在小鼠肝脏中的表达强烈增加，并且在HEK293细胞中的表达增加导致新生脂肪生成增加。这些数据支持SLC16A13与非酒精性脂肪性肝病和胰岛素抵抗的发展有关的观点。与这些数据一致，在我们使用CRISPR/Cas9产生的SLC16A13基因敲除小鼠中，受到饮食诱导的肥胖和NAFLD的保护。因此，我们假设SLC16A13通过影响单羧酸盐的运输而参与肥胖、非酒精性脂肪性肝病和胰岛素抵抗的发展，单羧酸盐是各种肝脏流量的底物。根据我们的建议，SLC16A13转运体的底物和动力学将通过在高表达HEK293的SLC16A13细胞中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，将测定SLC16A13在肝脏和脂肪组织中的表达，在有无T2D的患者中。我们的数据将为候选基因SLC16A13如何导致2型糖尿病、NAFLD和肥胖症提供新的信息，以及其功能降低是否可能成为治疗非酒精性脂肪性肝病、T2D和肥胖症的新策略。

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.