%0 Journal Article %A Robert S Jones %A Chengjian Tu %A Ming Zhang %A Jun Qu %A Marilyn E. Morris %T Characterization and proteomic-transcriptomic investigation of Monocarboxylate Transporter 6 (Mct6) knockout mice: Evidence of a potential role in glucose and lipid metabolism %D 2019 %R 10.1124/mol.119.116731 %J Molecular Pharmacology %P mol.119.116731 %X Monocarboxylate transporter 6 (MCT6, SLC16A5) is an orphan transporter with no known endogenous substrates or physiological role. Previous in vitro and in vivo experiments investigated MCT6 substrate/inhibitor specificity in X. laevis oocytes; however, these data remain limited. Transcriptomic changes in the livers of mice undergoing different dieting schemes have suggested that Mct6 plays a role in glucose and lipid metabolism. The objectives of this study were (1) to develop a novel knockout mouse model (Mct6-/-) using CRISPR/Cas9 technology and (2) to characterize the KO animal model by examining physiological and biochemical parameters, and through global proteomic and liver transcriptomic profiling, to understand the physiological role of MCT6 in vivo. mRNA tissue analysis demonstrated knockout of Mct6, which showed greater than 90% knockdown of Mct6 (Slc16a5) gene expression in all major tissues analyzed when normalized to Mct6+/+ mice. Proteomic analyses identified greater than 4,000 unique proteins in kidney, liver, and colon tissues, among which 51, 38, and 241 proteins were significantly altered (respectively for each tissue) between Mct6+/+ and Mct6-/- mice. Additionally, Mct6-/- mice demonstrated significant changes in 199 genes in the liver compared with Mct6+/+ mice. In silico biological pathway analyses revealed significant changes in proteins and genes involved in glucose and lipid metabolism-associated pathways. This study is the first to provide evidence for an association of Mct6 in the regulation of glucose and lipid metabolism.SIGNIFICANCE STATEMENT This manuscript focuses on elucidating the innate biological role of an orphan transporter in vivo, which has not been investigated thus far. Using efficient and high throughput technologies, such as CRISPR/Cas9 gene editing, LC/MS/MS-based proteomic, and RNA-seq transcriptomic analyses, our laboratory provides the first existence and characterization of a Mct6 knockout mouse model. The evidence gathered in this manuscript, as well as other labs, support the importance of MCT6 in regulating a variety of glucose and lipid metabolic pathways, which may indicate its significance in metabolic diseases. %U https://molpharm.aspetjournals.org/content/molpharm/early/2019/07/10/mol.119.116731.full.pdf