Role of the carboxylate transporter SLC16A13 in energy and glucose homeostasis

• Applicant: Professor Dr. Andreas L. Birkenfeld
• Subject Area: Endocrinology, Diabetology, Metabolism ; Nutritional Sciences
• Term: from 2018 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 416575519

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.

• DFG Programme: Research Grants