Disruption of uridine homeostasis links liver pyrimidine metabolism to lipid accumulation

Journal of Lipid Research

Volumn 54, Issue 4, 2013, Pages 1044-1057

  Le, Thuc T ^a,b   Ziemba, Amy ^b   Urasaki, Yasuyo ^a,b   Hayes, Eugene ^b   Brotman, Steven ^b   Pizzorno, Giuseppe ^a,b  

^a DESERT RESEARCH INSTITUTE   (United States)

^b NEVADA CANCER INSTITUTE   (United States)

Author keywords

CARS microscopy; Fatty liver; Hepatic microvesicular steatosis; Liver lipid metabolism; Protein acetylation; Uridine phosphorylase

Indexed keywords

DIHYDROOROTATE DEHYDROGENASE; PYRIMIDINE; UNCLASSIFIED DRUG; URACIL; URIDINE; URIDINE PHOSPHORYLASE; URIDINE PHOSPHORYLASE 1;

ACETYLATION; AMINO ACID METABOLISM; ANIMAL CELL; ANIMAL TISSUE; ARTICLE; CATABOLISM; CELL FUNCTION; CELL METABOLISM; CONTROLLED STUDY; ENERGY METABOLISM; FATTY ACID METABOLISM; FATTY ACID OXIDATION; FATTY LIVER; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HOMEOSTASIS; HYDROLYSIS; LIPID METABOLISM; LIPID STORAGE; MALE; MEMBRANE DAMAGE; MITOCHONDRIAL MEMBRANE POTENTIAL; MOUSE; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN METABOLISM; PROTEIN SYNTHESIS; SIGNAL TRANSDUCTION; UPP1 GENE;

ANIMALS; CELLS, CULTURED; FATTY ACIDS; LIPID METABOLISM; LIVER; MALE; MICE; MICE, TRANSGENIC; PYRIMIDINES; TRIGLYCERIDES; URIDINE; URIDINE PHOSPHORYLASE;

EID: 84875832198     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M034249     Document Type: Article

References (53)

1. Alberts, B., A. Johnson, J. Lewis, M. Raff, K. Roberts, and P. Walter. 2008. Molecular Biology of the Cell. 5th edition. Garland Science, Taylor & Francis Group, NY.
2. Carver, J. D., and W. A. Walker. 1995. The role of nucleotides in human nutrition. J. Nutr. Biochem. 6 : 58-72.
3. Cantó, C., R. H. Houtkooper, E. Pirinen, D. Y. Youn, M. H. Oosterveer, Y. Cen, P. J. Fernandez-Marcos, H. Yamamoto, P. A. Andreux, P. Cettour-Rose, et al. 2012. The NAD(+) precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet-induced obesity. Cell Metab. 15 : 838-847.
4. Setzer, B., D. Lebrecht, and U. A. Walker. 2008. Pyrimidine nucleoside depletion sensitizes to the mitochondrial hepatotoxicity of the reverse transcriptase inhibitor stavudine. Am. J. Pathol. 172 : 681-690.
5. Traut, T. W., and M. E. Jones. 1996. Uracil metabolism-UMP synthesis from orotic acid or uridine and conversion of uracil to beta-Alanine: enzymes and cDNAs. Prog. Nucleic Acid Res. Mol. Biol. 53 : 1-78.
6. Connolly, G. P., and J. A. Duley. 1999. Uridine and its nucleotides: biological actions, therapeutic potentials. Trends Pharmacol. Sci. 20 : 218-225.
7. Löffl er, M., J. Jockel, G. Schuster, and C. Becker. 1997. Dihydroorotat-ubiquinone oxidoreductase links mitochondria in the biosynthesis of pyrimidine nucleotides. Mol. Cell. Biochem. 174 : 125-129.
8. Wallace, D. C. 2005. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine. Annu. Rev. Genet. 39 : 359-407.
9. Sutinen, J., U. A. Walker, K. Sevastianova, H. Klinker, A. M. Hakkinen, M. Ristola, and H. Yki-Jarvinen. 2007. Uridine supplementation for the treatment of antiretroviral therapy-Associated lipoatrophy: a randomized, double-blind, placebo-controlled trial. Antivir. Ther. 12 : 97-105.
10. Weinberg, M. E., M. C. Roman, P. Jacob, M. Wen, P. Cheung, U. A. Walker, K. Mulligan, and M. Schambelan. 2011. Enhanced uridine bioavailability following administration of a triacetyluridine-rich nutritional supplement. PLoS ONE. 6 : e14709.
11. Pizzorno, G., L. Yee, B. A. Burtness, J. C. Marsh, J. W. Darnowski, M. Y. Chu, S. H. Chu, E. Chu, J. J. Leffert, R. E. Handschumacher, et al. 1998. Phase I clinical and pharmacological studies of benzylacyclouridine, a uridine phosphorylase inhibitor. Clin. Cancer Res. 4 : 1165-1175.
12. van Groeningen, C. J., A. Leyva, I. Kraal, G. J. Peters, and H. M. Pinedo. 1986. Clinical and pharmacokinetic studies of prolonged administration of high-dose uridine intended for rescue from 5-FU toxicity. Cancer Treat. Rep. 70 : 745-750.
13. Traut, T. W. 1994. Physiological concentrations of purines and pyrimidines. Mol. Cell. Biochem. 140 : 1-22.
14. Gasser, T., J. D. Moyer, and R. E. Handschumacher. 1981. Novel singlepass exchange of circulating uridine in rat liver. Science. 213 : 777-778.
15. Cao, D., J. J. Leffert, J. McCabe, B. Kim, and G. Pizzorno. 2005. Abnormalities in uridine homeostatic regulation and pyrimidine nucleotide metabolism as a consequence of the deletion of the uridine phosphorylase gene. J. Biol. Chem. 280 : 21169-21175.
16. Cao, D., A. Ziemba, J. McCabe, R. Yan, L. Wan, B. Kim, M. Gach, S. Flynn, and G. Pizzorno. 2011. Differential expression of uridine phosphorylase in tumors contributes to an improved fl uoropyrimidine therapeutic activity. Mol. Cancer Ther. 10 : 2330-2339.
17. Soriano, P. 1999. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21 : 70-71.
18. Okabe, M., M. Ikawa, K. Kominami, T. Nakanishi, and Y. Nishimune. 1997. 'Green mice' as a source of ubiquitous green cells. FEBS Lett. 407 : 313-319.
19. Cao, D., R. L. Russell, D. Zhang, J. J. Leffert, and G. Pizzorno. 2002. Uridine phosphorylase (-/-) murine embryonic stem cells clarify the key role of this enzyme in the regulation of the pyrimidine salvage pathway and in the activation of fl uoropyrimidines. Cancer Res. 62 : 2313-2317.
20. Pizzorno, G., R. A. Wiegand, S. K. Lentz, and R. E. Handschumacher. 1992. Brequinar potentiates 5-fl uorouracil antitumor activity in a murine model colon 38 tumor by tissue-specifi c modulation of uridine nucleotide pools. Cancer Res. 52 : 1660-1665.
21. Samburova, V., M. S. Lemos, S. Hiibel, S. K. Hoekman, J. C. Cushman, and B. Zielinska. 2013. Analysis of triacylglycerols and free fatty acids in algae using ultra-performance liquid chromatography mass spectrometry. J. Am. Oil Chem. Soc. 90 : 53-64.
22. Seglen, P. O. 1976. Preparation of isolated rat liver cells. Methods Cell Biol. 13 : 29-83.
23. Urasaki, Y., M. G. Johlfs, R. R. Fiscus, and T. T. Le. 2012. Imaging immune and metabolic cells of visceral adipose tissues with multimodal nonlinear optical microscopy. PLoS ONE. 7 : e38418.
24. Le, T. T., A. Ziemba, Y. Urasaki, S. Brotman, and G. Pizzorno. 2012. Label-free evaluation of hepatic microvesicular steatosis with multimodal coherent anti-Stokes Raman scattering microscopy. PLoS ONE. 7 : e51092.
25. Evans, C. L., and X. S. Xie. 2008. Coherent anti-Stokes Raman scattering microscopy: chemically selective imaging for biology and medicine. Annu. Rev. Anal. Chem. 1 : 883-909.
26. Le, T. T., S. Yue, and J. X. Cheng. 2010. Shedding new light on lipid biology with coherent anti-Stokes Raman scattering microscopy. J. Lipid Res. 51 : 3091-3102.
27. Baldwin, J., A. M. Farajallah, N. A. Malmquist, P. K. Rathod, and M. A. Phillips. 2002. Malarial dihydroorotate dehydrogenase. Substrate and inhibitor specifi city. J. Biol. Chem. 277 : 41827-41834.
28. Baldwin, J., C. H. Michnoff, N. A. Malmquist, J. White, M. G. Roth, P. K. Rathod, and M. A. Phillips. 2005. High-throughput screening for potent and selective inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase. J. Biol. Chem. 280 : 21847-21853.
29. Moon, A., and W. J. Rhead. 1987. Complementation analysis of fatty acid oxidation disorders. J. Clin. Invest. 79 : 59-64.
30. Walker, U. A., M. Auclair, D. Lebrecht, M. Kornprobst, J. Capeau, and M. Caron. 2006. Uridine abrogates the adverse effects of antiretroviral pyrimidine analogues on adipose cell functions. Antivir. Ther. 11 : 25-34.
31. Khutornenko, A. A., V. V. Roudko, B. V. Chernyak, A. B. Vartapetian, P. M. Chumakov, and A. G. Evstafi eva. 2010. Pyrimidine biosynthesis links mitochondrial respiration to the p53 pathway. Proc. Natl. Acad. Sci. USA. 107 : 12828-12833.
32. Pizzorno, G., D. Cao, J. J. Leffert, R. L. Russell, D. Zhang, and R. E. Handschumacher. 2002. Homeostatic control of uridine and the role of uridine phosphorylase: a biological and clinical update. Biochim. Biophys. Acta. 1587 : 133-144.
33. Knecht, W., J. Henseling, and M. Loffl er. 2000. Kinetics of inhibition of human and rat dihydroorotate dehydrogenase by atovaquone, lawsone derivatives, brequinar sodium and polyporic acid. Chem. Biol. Interact. 124 : 61-76.
34. Lombard, D. B., F. W. Alt, H. L. Cheng, J. Bunkenborg, R. S. Streeper, R. Mostoslavsky, J. Kim, G. Yancopoulos, D. Valenzuela, A. Murphy, et al. 2007. Mammalian Sir2 homolog SIRT3 regulates global mitochondrial lysine acetylation. Mol. Cell. Biol. 27 : 8807-8814.
35. Hirschey, M. D., T. Shimazu, E. Jing, C. A. Grueter, A. M. Collins, B. Aouizerat, A. Stancakova, E. Goetzman, M. M. Lam, B. Schwer, et al. 2011. SIRT3 defi ciency and mitochondrial protein hyperacetylation accelerate the development of the metabolic syndrome. Mol. Cell. 44 : 177-190.
36. Kendrick, A. A., M. Choudhury, S. M. Rahman, C. E. McCurdy, M. Friederich, J. L. Van Hove, P. A. Watson, N. Birdsey, J. Bao, D. Gius, et al. 2011. Fatty liver is associated with reduced SIRT3 activity and mitochondrial protein hyperacetylation. Biochem. J. 433 : 505-514.
37. Blander, G., and L. Guarente. 2004. The Sir2 family of protein deacetylases. Annu. Rev. Biochem. 73 : 417-435.
38. Zhao, S., W. Xu, W. Jiang, W. Yu, Y. Lin, T. Zhang, J. Yao, L. Zhou, Y. Zeng, H. Li, et al. 2010. Regulation of cellular metabolism by protein lysine acetylation. Science. 327 : 1000-1004.
39. Kim, S. C., R. Sprung, Y. Chen, Y. Xu, H. Ball, J. Pei, T. Cheng, Y. Kho, H. Xiao, L. Xiao, et al. 2006. Substrate and functional diversity of lysine acetylation revealed by a proteomics survey. Mol. Cell. 23 : 607-618.
40. Fritz, K. S., J. J. Galligan, M. D. Hirschey, E. Verdin, and D. R. Petersen. 2012. Mitochondrial acetylome analysis in a mouse model of alcohol-induced liver injury utilizing SIRT3 knockout mice. J. Proteome Res. 11 : 1633-1643.
41. Creasey, W. A., L. Hankin, and R. E. Handschumacher. 1961. Fatty livers induced by orotic acid. I. Accumulation and metabolism of lipids. J. Biol. Chem. 236 : 2064-2070.
42. Jung, E. J., S. W. Kwon, B. H. Jung, S. H. Oh, and B. H. Lee. 2011. Role of the AMPK/SREBP-1 pathway in the development of orotic acid-induced fatty liver. J. Lipid Res. 52 : 1617-1625.
43. Becroft, D. M., L. I. Phillips, and A. Simmonds. 1969. Hereditary orotic aciduria: long-term therapy with uridine and a trial of uracil. J. Pediatr. 75 : 885-891.
44. Hirschey, M. D., T. Shimazu, E. Goetzman, E. Jing, B. Schwer, D. B. Lombard, C. A. Grueter, C. Harris, S. Biddinger, O. R. Ilkayeva, et al. 2010. SIRT3 regulates mitochondrial fatty-Acid oxidation by reversible enzyme deacetylation. Nature. 464 : 121-125.
45. Schwer, B., M. Eckersdorff, Y. Li, J. C. Silva, D. Fermin, M. V. Kurtev, C. Giallourakis, M. J. Comb, F. W. Alt, and D. B. Lombard. 2009. Calorie restriction alters mitochondrial protein acetylation. Aging Cell. 8 : 604-606.
46. Xiong, Y., and K. L. Guan. 2012. Mechanistic insights into the regulation of metabolic enzymes by acetylation. J. Cell Biol. 198 : 155-164.
47. Zhang, Y., J. J. Repa, Y. Inoue, G. P. Hayhurst, F. J. Gonzalez, and D. J. Mangelsdorf. 2004. Identifi cation of a liver-specifi c uridine phosphorylase that is regulated by multiple lipid-sensing nuclear receptors. Mol. Endocrinol. 18 : 851-862.
48. Lavine, J. E., and J. B. Schwimmer. 2004. Nonalcoholic fatty liver disease in the pediatric population. Clin. Liver Dis. 8 : 549-558, viii-ix.
49. Williams, C. D., J. Stengel, M. I. Asike, D. M. Torres, J. Shaw, M. Contreras, C. L. Landt, and S. A. Harrison. 2011. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-Aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology. 140 : 124-131.
50. Petersen, K. F., D. Befroy, S. Dufour, J. Dziura, C. Ariyan, D. L. Rothman, L. DiPietro, G. W. Cline, and G. I. Shulman. 2003. Mitochondrial dysfunction in the elderly: possible role in insulin resistance. Science. 300 : 1140-1142.
51. Begriche, K., J. Massart, M. A. Robin, A. Borgne-Sanchez, and B. Fromenty. 2011. Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver. J. Hepatol. 54 : 773-794.
52. Cohen, J. C., J. D. Horton, and H. H. Hobbs. 2011. Human fatty liver disease: old questions and new insights. Science. 332 : 1519-1523.
53. Angulo, P. 2002. Treatment of nonalcoholic fatty liver disease. Ann. Hepatol. 1 : 12-19.