Amino Acids

, Volume 48, Issue 8, pp 1983–1991 | Cite as

Creatine supplementation as a possible new therapeutic approach for fatty liver disease: early findings

  • Rafael DeminiceEmail author
  • Gabriela S. de Castro
  • Margaret E. Brosnan
  • John T. Brosnan
Minireview Article
Part of the following topical collections:
  1. Creatine


Over the last few years, consistent data have demonstrated that creatine (Cr) supplementation prevents the accumulation of fat in rat liver as well as the progression of fatty liver disease in different situations. Studies have demonstrated that Cr is effective and prevents fatty liver in high-fat and choline-deficient diets and in hepatoma cells in vitro. Because Cr synthesis is responsible for a considerable consumption of hepatic methyl groups, studies have tested the idea that Cr supplementation could modulate phospholipid formation and VLDL secretion. Studies have also demonstrated Cr is able to modulate the expression of key genes related to fatty acid oxidation in hepatocyte cell culture and in rat liver. However, to date, the mechanism by which Cr exerts protective effects against fatty liver is poorly understood. Therefore, the present review aims to summarize the studies involving the therapeutic use of Cr supplementation on fatty liver disease and to explore the mechanisms involved in one-carbon and fatty acid metabolism for the preventive effects of Cr supplementation on fat liver accumulation. Although a small number of studies have been conducted to date, we consider Cr as a new and promising therapeutic strategy to control fat accumulation in the liver as well as the progression of fatty liver disease.


NAFLD Fatty liver disease Creatine supplementation Β-oxidation De novo fatty acid synthesis Oxidative stress 



AMP-activated protein kinase


Betaine-homocysteine S-methyltransferase


Creatine kinase


De novo lipogenesis




Non-alcoholic fatty liver disease


Non-alcoholic steatohepatitis


Non-esterified fatty acids


Phosphatidylethanolamine N-methyltranferase











Deminice R is suported by Brazilian Grant from Coordenação de Aperfeiçoamento de Pessoal do Ensino Superior (Capes: 88881.068035/2014-01); de Castro GS is supported by Science without Borders Program—Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (246567/2013-9). Brosnan JT and Brosnan ME are supported by grant #97851 from the Canadian Institutes for Health Research.

Compliance with ethical standards

Conflict of interest

All authors declared that there is no potential conflict of interests regarding this article. Authors declare that this manuscript is a review and did not involve any humans and/or animal research.


  1. Abdelmegeed MA, Yoo SH, Henderson LE, Gonzalez FJ, Woodcroft KJ, Song BJ (2011) PPARα expression protects male mice from high fat-induced nonalcoholic fatty liver. J Nutr 141(4):603–610. doi: 10.3945/jn.110.135210 CrossRefPubMedPubMedCentralGoogle Scholar
  2. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPARγ signaling and metabolism: the good, the bad and the future. Nat Med 19(5):557–566. doi: 10.1038/nm.3159 CrossRefPubMedGoogle Scholar
  3. Al Rajabi A, Castro GS, da Silva RP, Nelson RC, Thiesen A, Vannucchi H, Vine DF, Proctor SD, Field CJ, Curtis JM, Jacobs RL (2014) Choline supplementation protects against liver damage by normalizing cholesterol metabolism in Pemt/Ldlr knockout mice fed a high-fat diet. J Nutr 144(3):252–257. doi: 10.3945/jn.113.185389 CrossRefPubMedGoogle Scholar
  4. Alves CR, Ferreira JC, de Siqueira-Filho MA, Carvalho CR, Lancha AH Jr, Gualano B (2012) Creatine-induced glucose uptake in type 2 diabetes: a role for AMPK-alpha? Amino Acids 43(4):1803–1807. doi: 10.1007/s00726-012-1246-6 CrossRefPubMedGoogle Scholar
  5. Bessman SP, Carpenter CL (1985) The creatine-creatine phosphate energy shuttle. Annu Rev Biochem 54:831–862. doi: 10.1146/ CrossRefPubMedGoogle Scholar
  6. Brosnan JT, Brosnan ME (2007) Creatine: endogenous metabolite, dietary, and therapeutic supplement. Annu Rev Nutr 27:241–261. doi: 10.1146/annurev.nutr.27.061406.093621 CrossRefPubMedGoogle Scholar
  7. Brosnan JT, da Silva RP, Brosnan ME (2011) The metabolic burden of creatine synthesis. Amino Acids 40(5):1325–1331. doi: 10.1007/s00726-011-0853-y CrossRefPubMedGoogle Scholar
  8. Caballero F, Fernandez A, Matias N, Martinez L, Fucho R, Elena M, Caballeria J, Morales A, Fernandez-Checa JC, Garcia-Ruiz C (2010) Specific contribution of methionine and choline in nutritional nonalcoholic steatohepatitis: impact on mitochondrial S-adenosyl-l-methionine and glutathione. J Biol Chem 285(24):18528–18536. doi: 10.1074/jbc.M109.099333 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Ceddia RB, Sweeney G (2004) Creatine supplementation increases glucose oxidation and AMPK phosphorylation and reduces lactate production in L6 rat skeletal muscle cells. J Physiol 555:409–421. doi: 10.1113/jphysiol.2003.056291 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Choe CU, Nabuurs C, Stockebrand MC, Neu A, Nunes P, Morellini F, Sauter K, Schillemeit S, Hermans-Borgmeyer I, Marescau B, Heerschap A, Isbrandt D (2013) L-arginine:glycine amidinotransferase deficiency protects from metabolic syndrome. Hum Mol Genet 22(1):110–123. doi: 10.1093/hmg/dds407 CrossRefPubMedGoogle Scholar
  11. da Silva RP, Nissim I, Brosnan ME, Brosnan JT (2009) Creatine synthesis: hepatic metabolism of guanidinoacetate and creatine in the rat in vitro and in vivo. Am J Physiol Endocrinol Metab 296(2):E256–E261. doi: 10.1152/ajpendo.90547.2008 CrossRefPubMedGoogle Scholar
  12. da Silva RP, Kelly KB, Leonard KA, Jacobs RL (2014) Creatine reduces hepatic TG accumulation in hepatocytes by stimulating fatty acid oxidation. Biochim Biophys Acta 1841 11:1639–1646. doi: 10.1016/j.bbalip.2014.09.001 CrossRefGoogle Scholar
  13. Day CP, James OF (1998) Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842–845CrossRefPubMedGoogle Scholar
  14. Deminice R, Portari GV, Vannucchi H, Jordao AA (2009) Effects of creatine supplementation on homocysteine levels and lipid peroxidation in rats. Br J Nutr 102(1):110–116. doi: 10.1017/S0007114508162985 CrossRefPubMedGoogle Scholar
  15. Deminice R, da Silva RP, Lamarre SG, Brown C, Furey GN, McCarter SA, Jordao AA, Kelly KB, King-Jones K, Jacobs RL, Brosnan ME, Brosnan JT (2011) Creatine supplementation prevents the accumulation of fat in the livers of rats fed a high-fat diet. J Nutr 141(10):1799–1804. doi: 10.3945/jn.111.144857 CrossRefPubMedGoogle Scholar
  16. Deminice R, da Silva RP, Lamarre SG, Kelly KB, Jacobs RL, Brosnan ME, Brosnan JT (2015a) Betaine supplementation prevents fatty liver induced by a high-fat diet: effects on one-carbon metabolism. Amino Acids 47(4):839–846. doi: 10.1007/s00726-014-1913-x CrossRefPubMedGoogle Scholar
  17. Deminice R, de Castro GS, Francisco LV, da Silva LE, Cardoso JF, Frajacomo FT, Teodoro BG, Dos Reis Silveira L, Jordao AA (2015b) Creatine supplementation prevents fatty liver in rats fed choline-deficient diet: a burden of one-carbon and fatty acid metabolism. J Nutr Biochem 26(4):391–397. doi: 10.1016/j.jnutbio.2014.11.014 CrossRefPubMedGoogle Scholar
  18. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Investig 115(5):1343–1351. doi: 10.1172/JCI23621 CrossRefPubMedPubMedCentralGoogle Scholar
  19. Earnest CP, Almada AL, Mitchell TL (1996) High-performance capillary electrophoresis-pure creatine monohydrate reduces blood lipids in men and women. Clin Sci 91(1):113–118CrossRefPubMedGoogle Scholar
  20. Edison EE, Brosnan ME, Meyer C, Brosnan JT (2007) Creatine synthesis: production of guanidinoacetate by the rat and human kidney in vivo. Am J Physiol Renal Physiol 293(6):F1799–F1804. doi: 10.1152/ajprenal.00356.2007 CrossRefPubMedGoogle Scholar
  21. Gao Q, Jia Y, Yang G, Zhang X, Boddu PC, Petersen B, Narsingam S, Zhu YJ, Thimmapaya B, Kanwar YS, Reddy JK (2015) PPARα-deficient ob/ob obese mice become more obese and manifest severe hepatic steatosis due to decreased fatty acid oxidation. Am J Pathol 185(5):1396–1408. doi: 10.1016/j.ajpath.2015.01.018 CrossRefPubMedPubMedCentralGoogle Scholar
  22. Garcia-Ruiz C, Baulies A, Mari M, Garcia-Roves PM, Fernandez-Checa JC (2013) Mitochondrial dysfunction in non-alcoholic fatty liver disease and insulin resistance: cause or consequence? Free Radical Res 47(11):854–868. doi: 10.3109/10715762.2013.830717 CrossRefGoogle Scholar
  23. Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, Nicol CJ, Vinson C, Gonzalez FJ, Reitman ML (2003) Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278(36):34268–34276. doi: 10.1074/jbc.M300043200 CrossRefPubMedGoogle Scholar
  24. Gawrieh S, Chalasani N (2015) Pharmacotherapy for nonalcoholic fatty liver disease. Semin Liver Dis 35(3):338–348. doi: 10.1055/s-0035-1562951 CrossRefPubMedGoogle Scholar
  25. Ghoshal AK, Ahluwalia M, Farber E (1983) The rapid induction of liver cell death in rats fed a choline-deficient methionine-low diet. Am J Pathol 113(3):309–314PubMedPubMedCentralGoogle Scholar
  26. Gualano B, Artioli GG, Poortmans JR, Lancha Junior AH (2010) Exploring the therapeutic role of creatine supplementation. Amino Acids 38(1):31–44. doi: 10.1007/s00726-009-0263-6 CrossRefPubMedGoogle Scholar
  27. Gualano B, Pinto AL, Perondi MB, Roschel H, Sallum AM, Hayashi AP, Solis MY, Silva CA (2011) Therapeutic effects of exercise training in patients with pediatric rheumatic diseases. Revista Brasileira de Reumatologia 51(5):490–496CrossRefPubMedGoogle Scholar
  28. Hardy T, Anstee QM, Day CP (2015) Nonalcoholic fatty liver disease: new treatments. Curr Opin Gastroenterol 31(3):175–183. doi: 10.1097/MOG.0000000000000175 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Harris RC, Soderlund K, Hultman E (1992) Elevation of creatine in resting and exercised muscle of normal subjects by creatine supplementation. Clin Sci 83(3):367–374CrossRefPubMedGoogle Scholar
  30. Jacobs RL, Lingrell S, Zhao Y, Francis GA, Vance DE (2008) Hepatic CTP:phosphocholine cytidylyltransferase-alpha is a critical predictor of plasma high density lipoprotein and very low density lipoprotein. J Biol Chem 283(4):2147–2155. doi: 10.1074/jbc.M706628200 CrossRefPubMedGoogle Scholar
  31. Jacobs RL, Zhao Y, Koonen DP, Sletten T, Su B, Lingrell S, Cao G, Peake DA, Kuo MS, Proctor SD, Kennedy BP, Dyck JR, Vance DE (2010) Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity. J Biol Chem 285(29):22403–22413. doi: 10.1074/jbc.M110.108514 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Jay MA, Ren J (2007) Peroxisome proliferator-activated receptor (PPAR) in metabolic syndrome and type 2 diabetes mellitus. Curr Diabet Rev 3(1):33–39CrossRefGoogle Scholar
  33. Johnson NA, George J (2010) Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology 52(1):370–381. doi: 10.1002/hep.23711 CrossRefPubMedGoogle Scholar
  34. Kawano Y, Cohen DE (2013) Mechanisms of hepatic triglyceride accumulation in non-alcoholic fatty liver disease. J Gastroenterol 48(4):434–441. doi: 10.1007/s00535-013-0758-5 CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kazak L, Chouchani ET, Jedrychowski MP, Erickson BK, Shinoda K, Cohen P, Vetrivelan R, Lu GZ, Laznik-Bogoslavski D, Hasenfuss SC, Kajimura S, Gygi SP, Spiegelman BM (2015) A creatine-driven substrate cycle enhances energy expenditure and thermogenesis in beige fat. Cell 22(3):643–655. doi: 10.1016/j.cell.2015.09.035 CrossRefGoogle Scholar
  36. Kharbanda KK, Mailliard ME, Baldwin CR, Beckenhauer HC, Sorrell MF, Tuma DJ (2007) Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidylethanolamine methyltransferase pathway. J Hepatol 46(2):314–321. doi: 10.1016/j.jhep.2006.08.024 CrossRefPubMedGoogle Scholar
  37. Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI (2011) Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci USA 108(39):16381–16385. doi: 10.1073/pnas.1113359108 CrossRefPubMedPubMedCentralGoogle Scholar
  38. Kwon do Y, Jung YS, Kim SJ, Park HK, Park JH, Kim YC (2009) Impaired sulfur-amino acid metabolism and oxidative stress in nonalcoholic fatty liver are alleviated by betaine supplementation in rats. J Nutr 139(1):63–68. doi: 10.3945/jn.108.094771
  39. Larson-Meyer DE, Heilbronn LK, Redman LM, Newcomer BR, Frisard MI, Anton S, Smith SR, Alfonso A, Ravussin E (2006) Effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects. Diabet Care 29(6):1337–1344. doi: 10.2337/dc05-2565 CrossRefGoogle Scholar
  40. Lavine JE, Schwimmer JB, Van Natta ML, Molleston JP, Murray KF, Rosenthal P, Abrams SH, Scheimann AO, Sanyal AJ, Chalasani N, Tonascia J, Unalp A, Clark JM, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR, Nonalcoholic Steatohepatitis Clinical Research N (2011) Effect of vitamin E or metformin for treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC randomized controlled trial. Jama 305(16):1659–1668. doi: 10.1001/jama.2011.520 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Lewis GF, Carpentier A, Adeli K, Giacca A (2002) Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 23(2):201–229. doi: 10.1210/edrv.23.2.0461 CrossRefPubMedGoogle Scholar
  42. Li Z, Agellon LB, Allen TM, Umeda M, Jewell L, Mason A, Vance DE (2006) The ratio of phosphatidylcholine to phosphatidylethanolamine influences membrane integrity and steatohepatitis. Cell Metab 3(5):321–331. doi: 10.1016/j.cmet.2006.03.007 CrossRefPubMedGoogle Scholar
  43. Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer B Jr, Reitman ML, Gonzalez FJ (2003) Liver-specific disruption of PPARγ in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Investig 111(5):737–747. doi: 10.1172/JCI17223 CrossRefPubMedPubMedCentralGoogle Scholar
  44. Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, Faga E, Silli B, Pagano G (2003) Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatology 37(4):909–916. doi: 10.1053/jhep.2003.50132 CrossRefPubMedGoogle Scholar
  45. Musso G, Gambino R, Cassader M, Pagano G (2010) A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 52(1):79–104. doi: 10.1002/hep.23623 CrossRefPubMedGoogle Scholar
  46. Noureddin M, Mato JM, Lu SC (2015) Nonalcoholic fatty liver disease: update on pathogenesis, diagnosis, treatment and the role of S-adenosylmethionine. Exp Biol Med 240(6):809–820. doi: 10.1177/1535370215579161 CrossRefGoogle Scholar
  47. Pastori D, Polimeni L, Baratta F, Pani A, Del Ben M, Angelico F (2015) The efficacy and safety of statins for the treatment of non-alcoholic fatty liver disease. Dig Liver Dis 47(1):4–11. doi: 10.1016/j.dld.2014.07.170 CrossRefPubMedGoogle Scholar
  48. Pontikos M, Lu QL, Morgan JE, Hardie DG, Partridge TA, Carling D (1998) Dual regulation of the AMP-activated protein kinase provides a novel mechanism for the control of creatine kinase in skeletal muscle. EMBO J 17:1688–1699CrossRefGoogle Scholar
  49. Postic C, Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Investig 118(3):829–838. doi: 10.1172/JCI34275 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Rotman Y, Koh C, Zmuda JM, Kleiner DE, Liang TJ, Nash CRN (2010) The association of genetic variability in patatin-like phospholipase domain-containing protein 3 (PNPLA3) with histological severity of nonalcoholic fatty liver disease. Hepatology 52(3):894–903. doi: 10.1002/hep.23759 CrossRefPubMedPubMedCentralGoogle Scholar
  51. Schwenger KJ, Allard JP (2014) Clinical approaches to non-alcoholic fatty liver disease. World J Gastroenterol WJG 20(7):1712–1723. doi: 10.3748/wjg.v20.i7.1712 CrossRefPubMedGoogle Scholar
  52. Scorletti E, Bhatia L, McCormick KG, Clough GF, Nash K, Hodson L, Moyses HE, Calder PC, Byrne CD, On behalf of the WSI (2014) Effects of purified eicosapentaenoic and docosahexaenoic acids in non-alcoholic fatty liver disease: Results from the *WELCOME study. Hepatology. doi: 10.1002/hep.27289 PubMedGoogle Scholar
  53. Selhub J (2002) Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Health Aging 6(1):39–42PubMedGoogle Scholar
  54. Song J, da Costa KA, Fischer LM, Kohlmeier M, Kwock L, Wang S, Zeisel SH (2005) Polymorphism of the PEMT gene and susceptibility to nonalcoholic fatty liver disease (NAFLD). FASEB J Off Publ Fed Am Soc Exp Biol 19(10):1266–1271. doi: 10.1096/fj.04-3580com Google Scholar
  55. Stead LM, Au KP, Jacobs RL, Brosnan ME, Brosnan JT (2001) Methylation demand and homocysteine metabolism: effects of dietary provision of creatine and guanidinoacetate. Am J Physiol Endocrinol Metab 281(5):E1095–E1100PubMedGoogle Scholar
  56. Stead LM, Brosnan JT, Brosnan ME, Vance DE, Jacobs RL (2006) Is it time to reevaluate methyl balance in humans? Am J Clin Nutr 83(1):5–10PubMedGoogle Scholar
  57. Stockebrand M, Sauter K, Neu A, Isbrandt D, Choe CU (2013) Differential regulation of AMPK activation in leptin- and creatine-deficient mice. FASEB J Off Publ Fed Am Soc Exp Biol 27(10):4147–4156. doi: 10.1096/fj.12-225136 Google Scholar
  58. Tailleux A, Wouters K, Staels B (2012) Roles of PPARs in NAFLD: potential therapeutic targets. Biochim Biophys Acta 1821 5:809–818. doi: 10.1016/j.bbalip.2011.10.016 CrossRefGoogle Scholar
  59. Takasawa K, Kubota N, Terauchi Y, Kadowaki T (2008) Impact of increased PPARγ activity in adipocytes in vivo on adiposity, insulin sensitivity and the effects of rosiglitazone treatment. Endocr J 55(4):767–776CrossRefPubMedGoogle Scholar
  60. Tilg H, Moschen AR (2010) Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52(5):1836–1846. doi: 10.1002/hep.24001 CrossRefPubMedGoogle Scholar
  61. Vance DE (2013) Physiological roles of phosphatidylethanolamine N-methyltransferase. Biochim Biophys Acta 1831(3):626–632. doi: 10.1016/j.bbalip.2012.07.017 CrossRefPubMedGoogle Scholar
  62. Viollet B, Guigas B, Leclerc J, Hébrard S, Lantier L, Mounier R, Andreelli F, Foretz M (2009) AMP-activated protein kinase in the regulation of hepatic energy metabolism: from physiology to therapeutic perspectives. Acta Physiol (Oxf) 196(1):81–98. doi: 10.1111/j.1748-1716.2009.01970.x CrossRefGoogle Scholar
  63. Vos MB, Lavine JE (2013) Dietary fructose in nonalcoholic fatty liver disease. Hepatology 57(6):2525–2531. doi: 10.1002/hep.26299 CrossRefPubMedGoogle Scholar
  64. Wallimann T, Tokarska-Schlattner M, Schlattner U (2011) The creatine kinase system and pleiotropic effects of creatine. Amino Acids 40(5):1271–1296. doi: 10.1007/s00726-011-0877-3 CrossRefPubMedPubMedCentralGoogle Scholar
  65. Wyss M, Kaddurah-Daouk R (2000) Creatine and creatinine metabolism. Physiol Rev 80(3):1107–1213PubMedGoogle Scholar
  66. Zhang Y, Cui Y, Wang XL, Shang X, Qi ZG, Xue J, Zhao X, Deng M, Xie ML (2015) PPARα/γ agonists and antagonists differently affect hepatic lipid metabolism, oxidative stress and inflammatory cytokine production in steatohepatitic rats. Cytokine 75(1):127–135. doi: 10.1016/j.cyto.2015.05.031 CrossRefPubMedGoogle Scholar
  67. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Wien 2016

Authors and Affiliations

  • Rafael Deminice
    • 1
    Email author
  • Gabriela S. de Castro
    • 2
  • Margaret E. Brosnan
    • 3
  • John T. Brosnan
    • 3
  1. 1.Department of Physical Education, Faculty of Physical Education and SportState University of LondrinaLondrinaBrazil
  2. 2.Human Development and Health Academic Unit, Faculty of MedicineUniversity of SouthamptonSouthamptonUK
  3. 3.Department of BiochemistryMemorial University of NewfoundlandSt. John’sCanada

Personalised recommendations