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Mct6) Knockout Mice: Evidence of a Potential Role in Glucose and Lipid Metabolism

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Mct6) Knockout Mice: Evidence of a Potential Role in Glucose and Lipid Metabolism Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 Characterization and proteomic-transcriptomic investigation of monocarboxylate transporter 6 (Mct6) knockout mice: evidence of a potential role in glucose and lipid metabolism Authors: Robert S. Jones 1, Chengjian Tu 1,2, Ming Zhang 2, Jun Qu 1,2, and Marilyn E. Morris 1, * 1 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York 14214, USA 2 New York State Center of Excellence in Bioinformatics and Life Sciences, 701 Ellicott Street, Downloaded from Buffalo, NY, USA molpharm.aspetjournals.org at ASPET Journals on October 1, 2021 1 Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 Running title: Mct6 knockout mice and role in glucose and lipid metabolism * Correspondence should be addressed to: Marilyn E. Morris, PhD Department of Pharmaceutical Sciences University at Buffalo State University of New York Downloaded from 352 Kapoor Hall Buffalo, NY 14214 molpharm.aspetjournals.org Ph: (716) 645-4839 [email protected] This manuscript contains: at ASPET Journals on October 1, 2021 23 text pages 5 tables 7 figures 54 references 226 words in Abstract 444 words in Introduction 1536 words in Discussion Nonstandard abbreviations: ALP: alkaline phosphatase, ALT: alanine aminotransferase, BUN: blood urea nitrogen, CRISPR/Cas9: clustered regularly interspaced short palindromic 2 Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 repeats/crispr associated protein 9, FAM: fluorescein amidite, FC: fold-change, Gapdh: glyceraldehyde 3-phosphate dehydrogenase, GLU: glucose, gRNA: guide RNA, Hprt: hypoxanthine guanine phosphoribosyl transferase, Indel: insertion/deletion, KO: knockout, LC/MS: liquid chromatography/mass spectrometry, Mct: monocarboxylate transporter, NGS: next generation sequencing, NHEJ: nonhomologous end joining, PAM: protospacer adjacent motif, PCA: principal component analysis, qRT-PCR: quantitative real time-polymerase chain reaction, Slc16a5: solute carrier family 16 member 5, TP: total protein, TG: triglycerides, WT: wildtype Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 1, 2021 3 Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 ABSTRACT 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 Downloaded from 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 molpharm.aspetjournals.org 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 at ASPET Journals on October 1, 2021 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. 4 Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 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. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 1, 2021 5 Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 INTRODUCTION The monocarboxylate transporter (MCT, SLC16) family of transporters consists of 14 isoforms, with MCTs 1-4 being extensively characterized (Jones and Morris, 2016). MCTs 1-4 transport essential monocarboxylate anions such as lactate and pyruvate, in a proton-dependent manner. Other MCT isoforms do not necessarily transport monocarboxylates, but are essential for the distribution of important endogenous compounds such as thyroid hormone to the brain (MCT8/10) (Abe et al., 2012; Dumitrescu et al., 2006; Friesema et al., 2003) and aromatic amino acids into cells (MCT10) (Halestrap and Meredith, Downloaded from 2004). Recent publications have identified potential clinical roles of MCT1/4 in cancer treatment, MCT8 in hypothyroidism-related Allan-Herndon-Dudley syndrome (Schwartz et al., 2005), MCT11 in diabetes (Rusu et al., 2017), and MCT12 in cataract development (Castorino et al., 2011; Dhayat et al., 2016). molpharm.aspetjournals.org However, a substantial number of MCTs have yet to be “de-orphanized”, and for these MCT transporters their physiological function and potential role in drug targeting or disease remains unknown. Monocarboxylate transporter 6 (MCT6, SLC16A5), classified as an orphan transporter protein, is expressed in tissues involved in drug absorption and elimination (Gill et al., 2005; Kohyama et al., 2013) at ASPET Journals on October 1, 2021 (note that Gil et. al refers to MCT6 as “MCT5” prior to changes in isoform nomenclature). Substantial changes in murine hepatic Slc16a5 gene expression occurs in different dieting states, including fasting (Zhang et al., 2011b) and fenofibrate-supplemented (Lu et al., 2011) diets. In the study evaluating the effects of fasting and fed diet on the murine liver transcriptome, Slc16a5 was detected as the 6th most upregulated gene that was induced by 24-h fasting, with approximately a 5- fold increase in gene expression compared to expression after a normal diet (Zhang et al., 2011a). This was also the most up-regulated solute carrier protein within this analysis. Treatment of mice with fenofibrate resulted in a 3- to 6-fold upregulation of Slc16a5 in murine liver (Lu et al., 2011). These data suggest that Mct6 may play a role in lipid metabolism due to its differential regulation following various diets. In terms of substrate specificity, our lab and others have reported that MCT6 substrates include bumetanide, nateglinide, probenecid, and prostaglandin F2α based on studies with human MCT6-transfected 6 Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 X. laevis oocytes (Murakami et al., 2005). A series of dietary aglycone flavonoids were also shown to be inhibitors of human MCT6-mediated bumetanide transport in X. laevis oocytes (Jones et al., 2017). The goal of this study was to develop a novel CRISPR/Cas9 knockout mouse model of Mct6 deficiency and perform comparisons with WT Mct6+/+ mice, including (1) physiological and biochemical parameters, (2) multi-tissue, global proteome profiling, and (3) a liver transcriptomic analysis. Pathway annotations were generated to better understand the physiological role of MCT6 in vivo. Downloaded from molpharm.aspetjournals.org at ASPET Journals on October 1, 2021 7 Molecular Pharmacology Fast Forward. Published on July 10, 2019 as DOI: 10.1124/mol.119.116731 This article has not been copyedited and formatted. The final version may differ from this version. MOL # 116731 MATERIALS AND METHODS Ethics Statement. Procedures involving mice were approved by and performed in accordance with the rules and recommendations of the Institutional Animal Care and Use Committee (IACUC) of the University at Buffalo. Animals. Downloaded from C56BL/6NCr and CD-1 mice were used for the in vivo studies (Charles
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