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Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5).

Huard K, Brown J, Jones JC, Cabral S, Futatsugi K, Gorgoglione M, Lanba A, Vera NB, Zhu Y, Yan Q, Zhou Y, Vernochet C, Riccardi K, Wolford A, Pirman D, Niosi M, Aspnes G, Herr M, Genung NE, Magee TV, Uccello DP, Loria P, Di L, Gosset JR, Hepworth D, Rolph T, Pfefferkorn JA, Erion DM - Sci Rep (2015)

Bottom Line: NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions.Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT.The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.

View Article: PubMed Central - PubMed

Affiliation: Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139.

ABSTRACT
Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.

No MeSH data available.


Related in: MedlinePlus

Effect in mice treated chronically with 2.(A) Plasma glucose concentrations during an OGTT following treatment for 20 days with 250 mg/kg BID compound 2 (*P < 0.05, n = 5 normal chow, n = 10 for each HFD group). (B) Plasma glucose concentrations AUC (***P < 0.005, One-way ANOVA – Dunnett’s post hoc test). (C) Plasma insulin concentrations AUC. (D–F) Hepatic triglycerides, diacylglycerides, and acyl-carnitines from livers of mice treated with 250 mg/kg BID compound 2 for 21 days (n = 5 normal chow, n = 10 for each HFD group, *P < 0.05, One-way ANOVA – Dunnett’s post hoc test).
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f5: Effect in mice treated chronically with 2.(A) Plasma glucose concentrations during an OGTT following treatment for 20 days with 250 mg/kg BID compound 2 (*P < 0.05, n = 5 normal chow, n = 10 for each HFD group). (B) Plasma glucose concentrations AUC (***P < 0.005, One-way ANOVA – Dunnett’s post hoc test). (C) Plasma insulin concentrations AUC. (D–F) Hepatic triglycerides, diacylglycerides, and acyl-carnitines from livers of mice treated with 250 mg/kg BID compound 2 for 21 days (n = 5 normal chow, n = 10 for each HFD group, *P < 0.05, One-way ANOVA – Dunnett’s post hoc test).

Mentions: Given these positive effects of 2 on plasma glucose concentrations, we subsequently treated mice fed a HFD for 21 days with either 250 mg/kg of 2 BID or vehicle. During an oral glucose tolerance test (OGTT), the HFD group had significant glucose intolerance compared to the normal chow fed mice. The glucose intolerance was completely reversed in the mice treated with 2 (Fig. 5A,B). During the OGTT there were no differences in plasma insulin concentrations area under the curve (Fig. 5C). In addition, livers of mice treated with 2 had a trend for lower hepatic TAG and DAG, with higher levels of acylcarnitine (Fig. 5D–F), which may be indicative of greater flux through β-oxidation pathways and was corroborated by a trend for increase β-hydroxybutyrate concentrations (Vehicle HFD: 0.40 ± 0.02 mmol/L and 2 HFD: 0.49 ± 0.06 mmol/L).


Discovery and characterization of novel inhibitors of the sodium-coupled citrate transporter (NaCT or SLC13A5).

Huard K, Brown J, Jones JC, Cabral S, Futatsugi K, Gorgoglione M, Lanba A, Vera NB, Zhu Y, Yan Q, Zhou Y, Vernochet C, Riccardi K, Wolford A, Pirman D, Niosi M, Aspnes G, Herr M, Genung NE, Magee TV, Uccello DP, Loria P, Di L, Gosset JR, Hepworth D, Rolph T, Pfefferkorn JA, Erion DM - Sci Rep (2015)

Effect in mice treated chronically with 2.(A) Plasma glucose concentrations during an OGTT following treatment for 20 days with 250 mg/kg BID compound 2 (*P < 0.05, n = 5 normal chow, n = 10 for each HFD group). (B) Plasma glucose concentrations AUC (***P < 0.005, One-way ANOVA – Dunnett’s post hoc test). (C) Plasma insulin concentrations AUC. (D–F) Hepatic triglycerides, diacylglycerides, and acyl-carnitines from livers of mice treated with 250 mg/kg BID compound 2 for 21 days (n = 5 normal chow, n = 10 for each HFD group, *P < 0.05, One-way ANOVA – Dunnett’s post hoc test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664966&req=5

f5: Effect in mice treated chronically with 2.(A) Plasma glucose concentrations during an OGTT following treatment for 20 days with 250 mg/kg BID compound 2 (*P < 0.05, n = 5 normal chow, n = 10 for each HFD group). (B) Plasma glucose concentrations AUC (***P < 0.005, One-way ANOVA – Dunnett’s post hoc test). (C) Plasma insulin concentrations AUC. (D–F) Hepatic triglycerides, diacylglycerides, and acyl-carnitines from livers of mice treated with 250 mg/kg BID compound 2 for 21 days (n = 5 normal chow, n = 10 for each HFD group, *P < 0.05, One-way ANOVA – Dunnett’s post hoc test).
Mentions: Given these positive effects of 2 on plasma glucose concentrations, we subsequently treated mice fed a HFD for 21 days with either 250 mg/kg of 2 BID or vehicle. During an oral glucose tolerance test (OGTT), the HFD group had significant glucose intolerance compared to the normal chow fed mice. The glucose intolerance was completely reversed in the mice treated with 2 (Fig. 5A,B). During the OGTT there were no differences in plasma insulin concentrations area under the curve (Fig. 5C). In addition, livers of mice treated with 2 had a trend for lower hepatic TAG and DAG, with higher levels of acylcarnitine (Fig. 5D–F), which may be indicative of greater flux through β-oxidation pathways and was corroborated by a trend for increase β-hydroxybutyrate concentrations (Vehicle HFD: 0.40 ± 0.02 mmol/L and 2 HFD: 0.49 ± 0.06 mmol/L).

Bottom Line: NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions.Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT.The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.

View Article: PubMed Central - PubMed

Affiliation: Worldwide Medicinal Chemistry, 610 Main street, Cambridge, MA 02139.

ABSTRACT
Citrate is a key regulatory metabolic intermediate as it facilitates the integration of the glycolysis and lipid synthesis pathways. Inhibition of hepatic extracellular citrate uptake, by blocking the sodium-coupled citrate transporter (NaCT or SLC13A5), has been suggested as a potential therapeutic approach to treat metabolic disorders. NaCT transports citrate from the blood into the cell coupled to the transport of sodium ions. The studies herein report the identification and characterization of a novel small dicarboxylate molecule (compound 2) capable of selectively and potently inhibiting citrate transport through NaCT, both in vitro and in vivo. Binding and transport experiments indicate that 2 specifically binds NaCT in a competitive and stereosensitive manner, and is recognized as a substrate for transport by NaCT. The favorable pharmacokinetic properties of 2 permitted in vivo experiments to evaluate the effect of inhibiting hepatic citrate uptake on metabolic endpoints.

No MeSH data available.


Related in: MedlinePlus