In a mammalian model, SLC13a5 knockout (KO) mice show improvements in glycemic control as demonstrated by increases in the glucose infusion rate required to maintain euglycemia in a hyperinsulinemic-euglycemic clamp, which can be attributed to suppression of glucose production 19. In these species, inactivation of SLC13a5 specifically resulted in lifespan extension, analogous to the results observed with caloric restriction. The regulation of metabolic processes by SLC13A5 was revealed through studies with its homolog in Drosophila melanogaster and Caenorhabditis elegans 16, 17, 18. The expression profile and reported substrate selectivity of NaCT make it an attractive target to alter hepatic citrate uptake 15. NaCT, on the other hand, is the only known plasma membrane carrier to preferentially transport citrate over dicarboxylates 14. SLC13A5 expression is enriched in the human liver and appears to be the predominant plasma membrane citrate transporter expressed 13. While these transporters bind citrate with a lower affinity than other Krebs cycle intermediates, NaDC1 and NaDC3 play an important role in the absorption and excretion of citrate 13. In humans, NaDC1 and NaDC3 are di- and tri-carboxylate transporters primarily expressed in the intestine and kidney. NaDC1, NaDC3 and NaCT (encoded by SLC13A2, SLC13A3 and SLC13A5, respectively) are critical carrier proteins that co-transport sodium ions with Krebs cycle intermediates such as citrate and succinate from the extracellular space into the cell 12. Blocking the cellular uptake of citrate is hypothesized to have beneficial metabolic effects by reducing the energy burden placed on cells 11. Citrate also promotes the polymerization and thus activation of acetyl-CoA carboxylase (ACC) 10, which catalyzes the rate limiting step in de novo lipogenesis (DNL). Through allosteric modulation, citrate inhibits phosphofructokinase (PFK), thereby reducing glycolytic flux 9. Alternative mechanisms capable of decreasing both hepatic lipid burden and glucose production remain of significant interest for the treatment of T2D.Ĭitrate is a key metabolite involved in intracellular signaling. More recently, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-IV) inhibitors have become well established diabetes treatments with demonstrated benefits on reducing hepatic fat as well 8. However, the side effects associated with TZDs such as weight gain and bone fractures have drastically reduced the use of this class of drugs 7. Thiazolidinediones (TZDs) used as anti-diabetes therapies exert multiple benefits on hepatic metabolism by reducing both liver fat and hepatic gluconeogenesis 5, 6. Additionally, increased liver fat associated with non-alcoholic fatty liver disease (NAFLD) is considered a pre-requisite for the development of non-alcoholic steatohepatitis (NASH) 4. Therapies that could simultaneously target both pathogenic elevations in liver fat and hyperglycemia, are highly desirable because in T2D, the elevations in circulating plasma glucose concentrations can be partially attributed to increased hepatic glucose production due to elevations in hepatic gluconeogenesis 1, 2, 3. Fatty liver is a frequent co-morbidity of type 2 diabetes (T2D) and obesity.
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