Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2003 Aug 15;374(Pt 1):21–26. doi: 10.1042/BJ20030827

Human sodium-coupled citrate transporter, the orthologue of Drosophila Indy, as a novel target for lithium action.

Katsuhisa Inoue 1, Lina Zhuang 1, Dennis M Maddox 1, Sylvia B Smith 1, Vadivel Ganapathy 1
PMCID: PMC1223593  PMID: 12826022

Abstract

NaCT (sodium-coupled citrate transporter) is an Na(+)-coupled citrate transporter identified recently in mammals that mediates the cellular uptake of citrate. It is expressed predominantly in the liver. NaCT is structurally and functionally related to the product of the Indy (I'm not dead yet) gene in Drosophila, the dysfunction of which leads to lifespan extension. Here, we show that NaCT mediates the utilization of extracellular citrate for fat synthesis in human liver cells, and that the process is stimulated by lithium. The transport function of NaCT is enhanced by lithium at concentrations found in humans treated with lithium for bipolar disorders. Valproate and carbamazepine, two other drugs that are used for the treatment of bipolar disorder, do not affect the function of NaCT. The stimulatory effect of Li+ is specific for human NaCT, since NaCTs from other animal species are either inhibited or unaffected by Li+. The data also suggest that two of the four Na(+)-binding sites in human NaCT may become occupied by Li+ to produce the stimulatory effect. The stimulation of NaCT in humans by lithium at therapeutically relevant concentrations has potential clinical implications. We also show here that a single base mutation in codon-500 (TTT-->CTT) in the human NaCT gene, leading to the replacement of phenylalanine with leucine, stimulates the transport function and abolishes the stimulatory effect of lithium. This raises the possibility that genetic mutations in humans may lead to alterations in the constitutive activity of the transporter, with associated clinical consequences.

Full Text

The Full Text of this article is available as a PDF (147.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Atmaca Murad, Kuloglu Murat, Tezcan Ertan, Ustundag Bilal. Weight gain and serum leptin levels in patients on lithium treatment. Neuropsychobiology. 2002;46(2):67–69. doi: 10.1159/000065414. [DOI] [PubMed] [Google Scholar]
  2. Baptista T., Teneud L., Contreras Q., Alastre T., Burguera J. L., de Burguera M., de Baptista E., Weiss S., Hernàndez L. Lithium and body weight gain. Pharmacopsychiatry. 1995 Mar;28(2):35–44. doi: 10.1055/s-2007-979586. [DOI] [PubMed] [Google Scholar]
  3. Bode Barrie P., Fuchs Bryan C., Hurley Bryan P., Conroy Jennifer L., Suetterlin Julie E., Tanabe Kenneth K., Rhoads David B., Abcouwer Steve F., Souba Wiley W. Molecular and functional analysis of glutamine uptake in human hepatoma and liver-derived cells. Am J Physiol Gastrointest Liver Physiol. 2002 Nov;283(5):G1062–G1073. doi: 10.1152/ajpgi.00031.2002. [DOI] [PubMed] [Google Scholar]
  4. Bond P. A., Jenner F. A., Lee C. R., Lenton E., Pollitt R. J., Sampson G. A. The effect of lithium salts on the urinary excretion of -oxoglutarate in man. Br J Pharmacol. 1972 Sep;46(1):116–123. doi: 10.1111/j.1476-5381.1972.tb06854.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen Y., Silverstone T. Lithium and weight gain. Int Clin Psychopharmacol. 1990 Jul;5(3):217–225. doi: 10.1097/00004850-199007000-00007. [DOI] [PubMed] [Google Scholar]
  6. Coxhead N., Silverstone T., Cookson J. Carbamazepine versus lithium in the prophylaxis of bipolar affective disorder. Acta Psychiatr Scand. 1992 Feb;85(2):114–118. doi: 10.1111/j.1600-0447.1992.tb01453.x. [DOI] [PubMed] [Google Scholar]
  7. Dietschy J. M., Turley S. D., Spady D. K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. J Lipid Res. 1993 Oct;34(10):1637–1659. [PubMed] [Google Scholar]
  8. Fagiolini Andrea, Frank Ellen, Houck Patricia R., Mallinger Alan G., Swartz Holly A., Buysse Daniel J., Ombao Hernando, Kupfer David J. Prevalence of obesity and weight change during treatment in patients with bipolar I disorder. J Clin Psychiatry. 2002 Jun;63(6):528–533. doi: 10.4088/jcp.v63n0611. [DOI] [PubMed] [Google Scholar]
  9. Heninger G. R., Mueller P. S. Carbohydrate metabolism in mania before and after lithium carbonate treatment. Arch Gen Psychiatry. 1970 Oct;23(4):310–319. doi: 10.1001/archpsyc.1970.01750040022004. [DOI] [PubMed] [Google Scholar]
  10. Inoue Katsuhisa, Fei You-Jun, Huang Wei, Zhuang Lina, Chen Zhong, Ganapathy Vadivel. Functional identity of Drosophila melanogaster Indy as a cation-independent, electroneutral transporter for tricarboxylic acid-cycle intermediates. Biochem J. 2002 Oct 15;367(Pt 2):313–319. doi: 10.1042/BJ20021132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Inoue Katsuhisa, Zhuang Lina, Ganapathy Vadivel. Human Na+ -coupled citrate transporter: primary structure, genomic organization, and transport function. Biochem Biophys Res Commun. 2002 Dec 6;299(3):465–471. doi: 10.1016/s0006-291x(02)02669-4. [DOI] [PubMed] [Google Scholar]
  12. Inoue Katsuhisa, Zhuang Lina, Maddox Dennis M., Smith Sylvia B., Ganapathy Vadivel. Structure, function, and expression pattern of a novel sodium-coupled citrate transporter (NaCT) cloned from mammalian brain. J Biol Chem. 2002 Aug 11;277(42):39469–39476. doi: 10.1074/jbc.M207072200. [DOI] [PubMed] [Google Scholar]
  13. Jungermann K., Katz N. Functional specialization of different hepatocyte populations. Physiol Rev. 1989 Jul;69(3):708–764. doi: 10.1152/physrev.1989.69.3.708. [DOI] [PubMed] [Google Scholar]
  14. Knauf Felix, Rogina Blanka, Jiang Zhirong, Aronson Peter S., Helfand Stephen L. Functional characterization and immunolocalization of the transporter encoded by the life-extending gene Indy. Proc Natl Acad Sci U S A. 2002 Oct 21;99(22):14315–14319. doi: 10.1073/pnas.222531899. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Li Xiaohua, Bijur Gautam N., Jope Richard S. Glycogen synthase kinase-3beta, mood stabilizers, and neuroprotection. Bipolar Disord. 2002 Apr;4(2):137–144. doi: 10.1034/j.1399-5618.2002.40201.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. NORDMANN J., NORDMANN R. Organic acids in blood and urine. Adv Clin Chem. 1961;4:53–120. doi: 10.1016/s0065-2423(08)60035-9. [DOI] [PubMed] [Google Scholar]
  17. Pajor A. M. Molecular properties of sodium/dicarboxylate cotransporters. J Membr Biol. 2000 May 1;175(1):1–8. doi: 10.1007/s002320001049. [DOI] [PubMed] [Google Scholar]
  18. Phiel C. J., Klein P. S. Molecular targets of lithium action. Annu Rev Pharmacol Toxicol. 2001;41:789–813. doi: 10.1146/annurev.pharmtox.41.1.789. [DOI] [PubMed] [Google Scholar]
  19. Price L. H., Heninger G. R. Lithium in the treatment of mood disorders. N Engl J Med. 1994 Sep 1;331(9):591–598. doi: 10.1056/NEJM199409013310907. [DOI] [PubMed] [Google Scholar]
  20. Rogina B., Reenan R. A., Nilsen S. P., Helfand S. L. Extended life-span conferred by cotransporter gene mutations in Drosophila. Science. 2000 Dec 15;290(5499):2137–2140. doi: 10.1126/science.290.5499.2137. [DOI] [PubMed] [Google Scholar]
  21. Scharnagl H., Schinker R., Gierens H., Nauck M., Wieland H., März W. Effect of atorvastatin, simvastatin, and lovastatin on the metabolism of cholesterol and triacylglycerides in HepG2 cells. Biochem Pharmacol. 2001 Dec 1;62(11):1545–1555. doi: 10.1016/s0006-2952(01)00790-0. [DOI] [PubMed] [Google Scholar]
  22. Shopsin B., Stern S., Gershon S. Altered carbohydrate metabolism during treatment with lithium carbonate. Absence of diagnostic specificity in hospitalized psychiatric patients. Arch Gen Psychiatry. 1972 Jun;26(6):566–571. doi: 10.1001/archpsyc.1972.01750240078012. [DOI] [PubMed] [Google Scholar]
  23. Spady D. K., Dietschy J. M. Sterol synthesis in vivo in 18 tissues of the squirrel monkey, guinea pig, rabbit, hamster, and rat. J Lipid Res. 1983 Mar;24(3):303–315. [PubMed] [Google Scholar]
  24. Sproule Beth. Lithium in bipolar disorder: can drug concentrations predict therapeutic effect? Clin Pharmacokinet. 2002;41(9):639–660. doi: 10.2165/00003088-200241090-00002. [DOI] [PubMed] [Google Scholar]
  25. Wang H., Fei Y. J., Kekuda R., Yang-Feng T. L., Devoe L. D., Leibach F. H., Prasad P. D., Ganapathy V. Structure, function, and genomic organization of human Na(+)-dependent high-affinity dicarboxylate transporter. Am J Physiol Cell Physiol. 2000 May;278(5):C1019–C1030. doi: 10.1152/ajpcell.2000.278.5.C1019. [DOI] [PubMed] [Google Scholar]
  26. Williams R. S., Harwood A. J. Lithium therapy and signal transduction. Trends Pharmacol Sci. 2000 Feb;21(2):61–64. doi: 10.1016/s0165-6147(99)01428-5. [DOI] [PubMed] [Google Scholar]
  27. Williams Robin S. B., Cheng Lili, Mudge Anne W., Harwood Adrian J. A common mechanism of action for three mood-stabilizing drugs. Nature. 2002 May 16;417(6886):292–295. doi: 10.1038/417292a. [DOI] [PubMed] [Google Scholar]
  28. Wright E. M., Wright S. H., Hirayama B., Kippen I. Interactions between lithium and renal transport of Krebs cycle intermediates. Proc Natl Acad Sci U S A. 1982 Dec;79(23):7514–7517. doi: 10.1073/pnas.79.23.7514. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES