Skip to main content

Advertisement

SpringerLink
Log in

Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Hereditary fructose intolerance (HFI) is a rare inborn disease characterized by a deficiency in aldolase B, which catalyzes the cleavage of fructose 1,6-bisphosphate and fructose 1-phosphate (Fru 1P) to triose molecules. In patients with HFI, ingestion of fructose results in accumulation of Fru 1P and depletion of ATP, which are believed to cause symptoms, such as nausea, vomiting, hypoglycemia, and liver and kidney failure. These sequelae can be prevented by a fructose-restricted diet. Recent studies in aldolase B-deficient mice and HFI patients have provided more insight into the pathogenesis of HFI, in particular the liver phenotype. Both aldolase B-deficient mice (fed a very low fructose diet) and HFI patients (treated with a fructose-restricted diet) displayed greater intrahepatic fat content when compared to controls. The liver phenotype in aldolase B-deficient mice was prevented by reduction in intrahepatic Fru 1P concentrations by crossing these mice with mice deficient for ketohexokinase, the enzyme that catalyzes the synthesis of Fru 1P. These new findings not only provide a potential novel treatment for HFI, but lend insight into the pathogenesis of fructose-induced non-alcoholic fatty liver disease (NAFLD), which has raised to epidemic proportions in Western society. This narrative review summarizes the most recent advances in the pathogenesis of HFI and discusses the implications for the understanding and treatment of fructose-induced NAFLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Chambers RA, Pratt RT (1956) Idiosyncrasy to fructose. Lancet 271(6938):340

    CAS  PubMed  Google Scholar 

  2. Herrs H, Joassin G (1961) Anomalie de l’aldolase hepatique dans l’intolerance au fructose. Enzymol Biol Clin 1:4–14

    Google Scholar 

  3. Li H, Byers HM, Diaz-Kuan A, Vos MB, Hall PL, Tortorelli S, Singh R, Wallenstein MB, Allain M, Dimmock DP, Farrell RM, McCandless S, Gambello MJ (2018) Acute liver failure in neonates with undiagnosed hereditary fructose intolerance due to exposure from widely available infant formulas. Mol Genet Metab 123(4):428–432. https://doi.org/10.1016/j.ymgme.2018.02.016

    Article  CAS  PubMed  Google Scholar 

  4. Sanchez-Lozada LG, Andres-Hernando A, Garcia-Arroyo FE, Cicerchi C, Li N, Kuwabara M, Roncal-Jimenez CA, Johnson RJ, Lanaspa MA (2019) Uric acid activates aldose reductase and the polyol pathway for endogenous fructose and fat production causing development of fatty liver in rats. J Biol Chem. https://doi.org/10.1074/jbc.RA118.006158

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yan LJ (2018) Redox imbalance stress in diabetes mellitus: role of the polyol pathway. Animal Model Exp Med 1(1):7–13. https://doi.org/10.1002/ame2.12001

    Article  PubMed  PubMed Central  Google Scholar 

  6. Odievre M, Gentil C, Gautier M, Alagille D (1978) Hereditary fructose intolerance in childhood. Diagnosis, management, and course in 55 patients. Am J Dis Child 132(6):605–608

    CAS  PubMed  Google Scholar 

  7. Baerlocher K, Gitzelmann R, Steinmann B, Gitzelmann-Cumarasamy N (1978) Hereditary fructose intolerance in early childhood: a major diagnostic challenge. Survey of 20 symptomatic cases. Helv Paediatr Acta 33(6):465–487

    CAS  PubMed  Google Scholar 

  8. Mock DM, Perman JA, Thaler M, Morris RC Jr (1983) Chronic fructose intoxication after infancy in children with hereditary fructose intolerance. A cause of growth retardation. N Engl J Med 309(13):764–770. https://doi.org/10.1056/nejm198309293091305

    Article  CAS  PubMed  Google Scholar 

  9. Ali M, Rellos P, Cox TM (1998) Hereditary fructose intolerance. J Med Genet 35(5):353–365

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Lebo RV, Tolan DR, Bruce BD, Cheung MC, Kan YW (1985) Spot-blot analysis of sorted chromosomes assigns a fructose intolerance disease locus to chromosome 9. Cytometry 6(5):478–483. https://doi.org/10.1002/cyto.990060513

    Article  CAS  PubMed  Google Scholar 

  11. Lench NJ, Telford EA, Andersen SE, Moynihan TP, Robinson PA, Markham AF (1996) An EST and STS-based YAC contig map of human chromosome 9q22.3. Genomics 38(2):199–205. https://doi.org/10.1006/geno.1996.0616

    Article  CAS  PubMed  Google Scholar 

  12. Cross NC, de Franchis R, Sebastio G, Dazzo C, Tolan DR, Gregori C, Odievre M, Vidailhet M, Romano V, Mascali G et al (1990) Molecular analysis of aldolase B genes in hereditary fructose intolerance. Lancet 335(8685):306–309

    CAS  PubMed  Google Scholar 

  13. Tolan DR, Brooks CC (1992) Molecular analysis of common aldolase B alleles for hereditary fructose intolerance in North Americans. Biochem Med Metab Biol 48(1):19–25

    CAS  PubMed  Google Scholar 

  14. Cross NC, Stojanov LM, Cox TM (1990) A new aldolase B variant, N334 K, is a common cause of hereditary fructose intolerance in Yugoslavia. Nucleic Acids Res 18(7):1925

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Coffee EM, Yerkes L, Ewen EP, Zee T, Tolan DR (2010) Increased prevalence of mutant null alleles that cause hereditary fructose intolerance in the American population. J Inherit Metab Dis 33(1):33–42. https://doi.org/10.1007/s10545-009-9008-7

    Article  PubMed  Google Scholar 

  16. Dazzo C, Tolan DR (1990) Molecular evidence for compound heterozygosity in hereditary fructose intolerance. Am J Hum Genet 46(6):1194–1199

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Cross NC, Tolan DR, Cox TM (1988) Catalytic deficiency of human aldolase B in hereditary fructose intolerance caused by a common missense mutation. Cell 53(6):881–885

    CAS  PubMed  Google Scholar 

  18. James CL, Rellos P, Ali M, Heeley AF, Cox TM (1996) Neonatal screening for hereditary fructose intolerance: frequency of the most common mutant aldolase B allele (A149P) in the British population. J Med Genet 33(10):837–841

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Gitzelmann R, Baerlocher K (1973) Vorteile und Nachteile der Fruktose in der Nahrung. Pädiat Fortbildk Praxis 37:40–55

    CAS  Google Scholar 

  20. Cox TM (1994) Aldolase B and fructose intolerance. FASEB J 8(1):62–71

    CAS  PubMed  Google Scholar 

  21. Tolan DR (1995) Molecular basis of hereditary fructose intolerance: mutations and polymorphisms in the human aldolase B gene. Hum Mutat 6(3):210–218. https://doi.org/10.1002/humu.1380060303

    Article  CAS  PubMed  Google Scholar 

  22. Hers H (1957) Le métabolisme du fructose. Editions Arscia, Bruxelles

    Google Scholar 

  23. Penhoet EE, Rutter WJ (1971) Catalytic and immunochemical properties of homomeric and heteromeric combinations of aldolase subunits. J Biol Chem 246(2):318–323

    CAS  PubMed  Google Scholar 

  24. Penhoet E, Rajkumar T, Rutter WJ (1966) Multiple forms of fructose diphosphate aldolase in mammalian tissues. Proc Natl Acad Sci USA 56(4):1275–1282

    CAS  PubMed  Google Scholar 

  25. Oppelt SA, Zhang W, Tolan DR (2017) Specific regions of the brain are capable of fructose metabolism. Brain Res 1657:312–322. https://doi.org/10.1016/j.brainres.2016.12.022

    Article  CAS  PubMed  Google Scholar 

  26. Steinmann B, Gitzelmann R (1981) The diagnosis of hereditary fructose intolerance. Helv Paediatr Acta 36(4):297–316

    CAS  PubMed  Google Scholar 

  27. Oberhaensli RD, Rajagopalan B, Taylor DJ, Radda GK, Collins JE, Leonard JV, Schwarz H, Herschkowitz N (1987) Study of hereditary fructose intolerance by use of 31P magnetic resonance spectroscopy. Lancet 2(8565):931–934

    CAS  PubMed  Google Scholar 

  28. Woods HF, Eggleston LV, Krebs HA (1970) The cause of hepatic accumulation of fructose 1-phosphate on fructose loading. Biochem J 119(3):501–510

    CAS  PubMed  PubMed Central  Google Scholar 

  29. van den Berghe G, Bronfman M, Vanneste R, Hers HG (1977) The mechanism of adenosine triphosphate depletion in the liver after a load of fructose. A kinetic study of liver adenylate deaminase. Biochem J 162(3):601–609

    PubMed  PubMed Central  Google Scholar 

  30. Kaufmann U, Froesch ER (1973) Inhibition of phosphorylase-a by fructose-1-phosphate, alpha-glycerophosphate and fructose-1,6-diphosphate: explanation for fructose-induced hypoglycaemia in hereditary fructose intolerance and fructose-1,6-diphosphatase deficiency. Eur J Clin Invest 3(5):407–413

    CAS  PubMed  Google Scholar 

  31. Thurston JH, Jones EM, Hauhart RE (1974) Decrease and inhibition of liver glycogen phosphorylase after fructose. An experimental model for the study of hereditary fructose intolerance. Diabetes 23(7):597–604

    CAS  PubMed  Google Scholar 

  32. Van Den Berghe G, Hue L, Hers HG (1973) Effect of administration of the fructose on the glycogenolytic action of glucagon. An investigation of the pathogeny of hereditary fructose intolerance. Biochem J 134(2):637–645

    Google Scholar 

  33. Van den Berghe G (1975) Biochemical aspects of hereditary fructose intolerance. In: Hommes FA, van den Berg CJ (eds) Normal and pathological development of energy metabolism. Academic Press, London, pp 221–228

    Google Scholar 

  34. Dubois RLH, Malaisse-Lagaw F, Toppet M (1965) Etude clinique et anatomo-pathologique de deux cas d’intolerance congenitale au fructose. Pediatrie 20:5–14

    Google Scholar 

  35. Rossier AMG, Colin J, Job J-C, Brault A, Beauvais P, Lemerle J (1966) Intolérance congénitale au fructose. deux cas damiliaux avec étude biochimique in vitro. Arch Fr Pediatr 23:533

    Google Scholar 

  36. Zalitis J, Oliver IT (1967) Inhibition of glucose phosphate isomerase by metabolic intermediates of fructose. Biochem J 102(3):753–759

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Froesch E, Prader A, Wolf H, Labhart A (1959) Die hereditare Fructoseintoleranz. Helvetica Paediatrica Acta 14:99–112

    CAS  PubMed  Google Scholar 

  38. Wilkening J, Nowack J, Decker K (1975) The dependence of glucose formation from lactate on the adenosine triphosphate content in the isolated perfused rat liver. Biochim Biophys Acta 392(2):299–309

    CAS  PubMed  Google Scholar 

  39. Gitzelmann R, Steinmann B, Gvd Berghe (1995) Disorders of Fructose Metabolism. In: Scriver C, Beaudet A, Sly W, Valle D (eds) The Metabolic and Molecular Basis of Inherited Disease. McGraw-Hill, New York, pp 905–934

    Google Scholar 

  40. Woods HF, Alberti KG (1972) Dangers of intravenous fructose. Lancet 2(7791):1354–1357

    CAS  PubMed  Google Scholar 

  41. Bergstrom J, Hultman E, Roch-Norlund AE (1968) Lactic acid accumulation in connection with fructose infusion. Acta Med Scand 184(5):359–364

    CAS  PubMed  Google Scholar 

  42. Lanaspa MA, Ishimoto T, Li N, Cicerchi C, Orlicky DJ, Ruzycki P, Rivard C, Inaba S, Roncal-Jimenez CA, Bales ES, Diggle CP, Asipu A, Petrash JM, Kosugi T, Maruyama S, Sanchez-Lozada LG, McManaman JL, Bonthron DT, Sautin YY, Johnson RJ (2013) Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome. Nat Commun 4:2434. https://doi.org/10.1038/ncomms3434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Johnson RJ, Rodriguez-Iturbe B, Roncal-Jimenez C, Lanaspa MA, Ishimoto T, Nakagawa T, Correa-Rotter R, Wesseling C, Bankir L, Sanchez-Lozada LG (2014) Hyperosmolarity drives hypertension and CKD–water and salt revisited. Nat Rev Nephrol 10(7):415–420. https://doi.org/10.1038/nrneph.2014.76

    Article  CAS  PubMed  Google Scholar 

  44. Roncal Jimenez CA, Ishimoto T, Lanaspa MA, Rivard CJ, Nakagawa T, Ejaz AA, Cicerchi C, Inaba S, Le M, Miyazaki M, Glaser J, Correa-Rotter R, Gonzalez MA, Aragon A, Wesseling C, Sanchez-Lozada LG, Johnson RJ (2014) Fructokinase activity mediates dehydration-induced renal injury. Kidney Int 86(2):294–302. https://doi.org/10.1038/ki.2013.492

    Article  CAS  PubMed  Google Scholar 

  45. Sward P, Rippe B (2012) Acute and sustained actions of hyperglycaemia on endothelial and glomerular barrier permeability. Acta Physiol (Oxf) 204(3):294–307. https://doi.org/10.1111/j.1748-1716.2011.02343.x

    Article  CAS  Google Scholar 

  46. Lyons PA, Gould S, Wise PH, Palmer TN (1991) Activation of erythrocyte aldose reductase in man in response to glycaemic challenge. Diabetes Res Clin Pract 14(1):9–13

    CAS  PubMed  Google Scholar 

  47. Oppelt SA, Sennott EM, Tolan DR (2015) Aldolase-B knockout in mice phenocopies hereditary fructose intolerance in humans. Mol Genet Metab 114(3):445–450. https://doi.org/10.1016/j.ymgme.2015.01.001

    Article  CAS  PubMed  Google Scholar 

  48. Lanaspa MA, Andres-Hernando A, Orlicky DJ, Cicerchi C, Jang C, Li N, Milagres T, Kuwabara M, Wempe MF, Rabinowitz JD, Johnson RJ, Tolan DR (2018) Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest 128(6):2226–2238. https://doi.org/10.1172/JCI94427

    Article  PubMed  PubMed Central  Google Scholar 

  49. Coffee E, Tolan D (2014) Gluconeogenesis. In: Lee B, Scaglia F (eds) Inborn errors of metabolism: from neonatal screening to metabolic pathways. Oxford University Press, New York, p 384

    Google Scholar 

  50. Agius L (2008) Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J 414(1):1–18. https://doi.org/10.1042/BJ20080595

    Article  CAS  PubMed  Google Scholar 

  51. Agius L, Peak M, Van Schaftingen E (1995) The regulatory protein of glucokinase binds to the hepatocyte matrix, but, unlike glucokinase, does not translocate during substrate stimulation. Biochem J 309(Pt 3):711–713

    CAS  PubMed  PubMed Central  Google Scholar 

  52. van Schaftingen E, Veiga-da-Cunha M, Niculescu L (1997) The regulatory protein of glucokinase. Biochem Soc Trans 25(1):136–140

    PubMed  Google Scholar 

  53. van Schaftingen E, Vandercammen A, Detheux M, Davies DR (1992) The regulatory protein of liver glucokinase. Adv Enzyme Regul 32:133–148

    PubMed  Google Scholar 

  54. Vandercammen A, Van Schaftingen E (1993) Species and tissue distribution of the regulatory protein of glucokinase. Biochem J 294(Pt 2):551–556

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Veiga-Da-Cunha M, Detheux M, Watelet N, Van Schaftingen E (1994) Cloning and expression of a Xenopus liver cDNA encoding a fructose-phosphate-insensitive regulatory protein of glucokinase. Eur J Biochem 225(1):43–51

    CAS  PubMed  Google Scholar 

  56. Beck T, Miller BG (2013) Structural basis for regulation of human glucokinase by glucokinase regulatory protein. Biochemistry 52(36):6232–6239. https://doi.org/10.1021/bi400838t

    Article  CAS  PubMed  Google Scholar 

  57. Choi JM, Seo MH, Kyeong HH, Kim E, Kim HS (2013) Molecular basis for the role of glucokinase regulatory protein as the allosteric switch for glucokinase. Proc Natl Acad Sci USA 110(25):10171–10176. https://doi.org/10.1073/pnas.1300457110

    Article  PubMed  Google Scholar 

  58. Jin ES, Lee MH, Murphy RE, Malloy CR (2018) Pentose phosphate pathway activity parallels lipogenesis but not antioxidant processes in rat liver. Am J Physiol Endocrinol Metab 314(6):E543–E551. https://doi.org/10.1152/ajpendo.00342.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lanaspa MA, Sanchez-Lozada LG, Choi YJ, Cicerchi C, Kanbay M, Roncal-Jimenez CA, Ishimoto T, Li N, Marek G, Duranay M, Schreiner G, Rodriguez-Iturbe B, Nakagawa T, Kang DH, Sautin YY, Johnson RJ (2012) Uric acid induces hepatic steatosis by generation of mitochondrial oxidative stress: potential role in fructose-dependent and -independent fatty liver. J Biol Chem 287(48):40732–40744. https://doi.org/10.1074/jbc.M112.399899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim MS, Krawczyk SA, Doridot L, Fowler AJ, Wang JX, Trauger SA, Noh HL, Kang HJ, Meissen JK, Blatnik M, Kim JK, Lai M, Herman MA (2016) ChREBP regulates fructose-induced glucose production independently of insulin signaling. J Clin Invest 126(11):4372–4386. https://doi.org/10.1172/JCI81993

    Article  PubMed  PubMed Central  Google Scholar 

  61. Hannou SA, Haslam DE, McKeown NM, Herman MA (2018) Fructose metabolism and metabolic disease. J Clin Invest 128(2):545–555. https://doi.org/10.1172/JCI96702

    Article  PubMed  PubMed Central  Google Scholar 

  62. Hayward BE, Bonthron DT (1998) Structure and alternative splicing of the ketohexokinase gene. Eur J Biochem 257(1):85–91

    CAS  PubMed  Google Scholar 

  63. Diggle CP, Shires M, Leitch D, Brooke D, Carr IM, Markham AF, Hayward BE, Asipu A, Bonthron DT (2009) Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem 57(8):763–774. https://doi.org/10.1369/jhc.2009.953190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Le MT, Lanaspa MA, Cicerchi CM, Rana J, Scholten JD, Hunter BL, Rivard CJ, Randolph RK, Johnson RJ (2016) Bioactivity-guided identification of botanical inhibitors of ketohexokinase. PLoS One 11(6):e0157458. https://doi.org/10.1371/journal.pone.0157458

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Aldamiz-Echevarria L, de Las Heras J, Couce ML, Alcalde C, Vitoria I, Bueno M, Blasco-Alonso J, Concepcion Garcia M, Ruiz M, Suarez R, Andrade F, Villate O (2019) Non-alcoholic fatty liver in hereditary fructose intolerance. Clin Nutr. https://doi.org/10.1016/j.clnu.2019.02.019

    Article  PubMed  Google Scholar 

  66. Marriott BP, Cole N, Lee E (2009) National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr 139(6):1228S–1235S. https://doi.org/10.3945/jn.108.098277

    Article  CAS  PubMed  Google Scholar 

  67. Simons N, Debray FG, Schaper NC, Kooi ME, Feskens EJM, Hollak CEM, Lindeboom L, Koek GH, Bons JAP, Lefeber DJ, Hodson L, Schalkwijk CG, Stehouwer CDA, Cassiman D, Brouwers M (2019) Patients with aldolase B deficiency are characterized by an increased intrahepatic triglyceride content. J Clin Endocrinol Metab. https://doi.org/10.1210/jc.2018-02795

    Article  PubMed  Google Scholar 

  68. Adamowicz M, Ploski R, Rokicki D, Morava E, Gizewska M, Mierzewska H, Pollak A, Lefeber DJ, Wevers RA, Pronicka E (2007) Transferrin hypoglycosylation in hereditary fructose intolerance: using the clues and avoiding the pitfalls. J Inherit Metab Dis 30(3):407. https://doi.org/10.1007/s10545-007-0569-z

    Article  CAS  PubMed  Google Scholar 

  69. Quintana E, Sturiale L, Montero R, Andrade F, Fernandez C, Couce ML, Barone R, Aldamiz-Echevarria L, Ribes A, Artuch R, Briones P (2009) Secondary disorders of glycosylation in inborn errors of fructose metabolism. J Inherit Metab Dis 32(Suppl 1):S273–S278. https://doi.org/10.1007/s10545-009-1219-4

    Article  PubMed  Google Scholar 

  70. Jaeken J, Pirard M, Adamowicz M, Pronicka E, van Schaftingen E (1996) Inhibition of phosphomannose isomerase by fructose 1-phosphate: an explanation for defective N-glycosylation in hereditary fructose intolerance. Pediatr Res 40(5):764–766. https://doi.org/10.1203/00006450-199611000-00017

    Article  CAS  PubMed  Google Scholar 

  71. Foster DW (2012) Malonyl-CoA: the regulator of fatty acid synthesis and oxidation. J Clin Invest 122(6):1958–1959

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Brouwers M, Jacobs C, Bast A, Stehouwer CDA, Schaper NC (2015) Modulation of glucokinase regulatory protein: a double-edged sword? Trends Mol Med 21(10):583–594. https://doi.org/10.1016/j.molmed.2015.08.004

    Article  CAS  PubMed  Google Scholar 

  73. Beer NL, Tribble ND, McCulloch LJ, Roos C, Johnson PR, Orho-Melander M, Gloyn AL (2009) The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver. Hum Mol Genet 18(21):4081–4088. https://doi.org/10.1093/hmg/ddp357

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Mahendran Y, Vangipurapu J, Cederberg H, Stancakova A, Pihlajamaki J, Soininen P, Kangas AJ, Paananen J, Civelek M, Saleem NK, Pajukanta P, Lusis AJ, Bonnycastle LL, Morken MA, Collins FS, Mohlke KL, Boehnke M, Ala-Korpela M, Kuusisto J, Laakso M (2013) Association of ketone body levels with hyperglycemia and type 2 diabetes in 9,398 Finnish men. Diabetes 62(10):3618–3626. https://doi.org/10.2337/db12-1363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S (2012) Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55(3):781–789. https://doi.org/10.1002/hep.24806

    Article  CAS  PubMed  Google Scholar 

  76. Santoro N, Caprio S, Pierpont B, Name MV, Savoye M, Parks EJ (2015) Hepatic de novo lipogenesis in obese youth is modulated by a common variant in the GCKR gene. J Clin Endocrinol Metab. https://doi.org/10.1210/jc.2015-1587

    Article  PubMed  PubMed Central  Google Scholar 

  77. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O’Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS, Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WH, Hirschhorn JN, Borecki IB (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 7(3):e1001324. https://doi.org/10.1371/journal.pgen.1001324

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Orho-Melander M, Melander O, Guiducci C, Perez-Martinez P, Corella D, Roos C, Tewhey R, Rieder MJ, Hall J, Abecasis G, Tai ES, Welch C, Arnett DK, Lyssenko V, Lindholm E, Saxena R, de Bakker PI, Burtt N, Voight BF, Hirschhorn JN, Tucker KL, Hedner T, Tuomi T, Isomaa B, Eriksson KF, Taskinen MR, Wahlstrand B, Hughes TE, Parnell LD, Lai CQ, Berglund G, Peltonen L, Vartiainen E, Jousilahti P, Havulinna AS, Salomaa V, Nilsson P, Groop L, Altshuler D, Ordovas JM, Kathiresan S (2008) Common missense variant in the glucokinase regulatory protein gene is associated with increased plasma triglyceride and C-reactive protein but lower fasting glucose concentrations. Diabetes 57(11):3112–3121. https://doi.org/10.2337/db08-0516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vaxillaire M, Cavalcanti-Proenca C, Dechaume A, Tichet J, Marre M, Balkau B, Froguel P, Group DS (2008) The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population. Diabetes 57(8):2253–2257. https://doi.org/10.2337/db07-1807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Bi M, Kao WH, Boerwinkle E, Hoogeveen RC, Rasmussen-Torvik LJ, Astor BC, North KE, Coresh J, Kottgen A (2010) Association of rs780094 in GCKR with metabolic traits and incident diabetes and cardiovascular disease: the ARIC Study. PLoS One 5(7):e11690. https://doi.org/10.1371/journal.pone.0011690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Simons N, Dekker JM, van Greevenbroek MM, Nijpels G, t Hart LM, van der Kallen CJ, Schalkwijk CG, Schaper NC, Stehouwer CD, Brouwers MC (2016) A common gene variant in glucokinase regulatory protein interacts with glucose metabolism on diabetic dyslipidemia: the combined CODAM and Hoorn studies. Diabetes Care 39(10):1811–1817. https://doi.org/10.2337/dc16-0153

    Article  CAS  PubMed  Google Scholar 

  82. Simons P, Simons N, Stehouwer CDA, Schalkwijk CG, Schaper NC, Brouwers M (2018) Association of common gene variants in glucokinase regulatory protein with cardiorenal disease: a systematic review and meta-analysis. PLoS One 13(10):e0206174. https://doi.org/10.1371/journal.pone.0206174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Bray GA, Nielsen SJ, Popkin BM (2004) Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79(4):537–543. https://doi.org/10.1093/ajcn/79.4.537

    Article  CAS  PubMed  Google Scholar 

  84. Bray GA (2008) Fructose: should we worry? Int J Obes (Lond) 32(Suppl 7):S127–S131. https://doi.org/10.1038/ijo.2008.248

    Article  CAS  Google Scholar 

  85. Stanhope KL, Havel PJ (2008) Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance. Curr Opin Lipidol 19(1):16–24. https://doi.org/10.1097/MOL.0b013e3282f2b24a

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Lustig RH (2010) Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc 110(9):1307–1321. https://doi.org/10.1016/j.jada.2010.06.008

    Article  CAS  PubMed  Google Scholar 

  87. Ludwig J, Viggiano TR, McGill DB, Oh BJ (1980) Nonalcoholic steatohepatitis: mayo clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55(7):434–438

    CAS  PubMed  Google Scholar 

  88. Targher G, Byrne CD, Lonardo A, Zoppini G, Barbui C (2016) Non-alcoholic fatty liver disease and risk of incident cardiovascular disease: a meta-analysis. J Hepatol 65(3):589–600. https://doi.org/10.1016/j.jhep.2016.05.013

    Article  PubMed  Google Scholar 

  89. Mantovani A, Byrne CD, Bonora E, Targher G (2018) Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care 41(2):372–382. https://doi.org/10.2337/dc17-1902

    Article  CAS  PubMed  Google Scholar 

  90. Stender S, Kozlitina J, Nordestgaard BG, Tybjaerg-Hansen A, Hobbs HH, Cohen JC (2017) Adiposity amplifies the genetic risk of fatty liver disease conferred by multiple loci. Nat Genet 49(6):842–847. https://doi.org/10.1038/ng.3855

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Zhang L, Perdomo G, Kim DH, Qu S, Ringquist S, Trucco M, Dong HH (2008) Proteomic analysis of fructose-induced fatty liver in hamsters. Metabolism 57(8):1115–1124. https://doi.org/10.1016/j.metabol.2008.03.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Mock K, Lateef S, Benedito VA, Tou JC (2017) High-fructose corn syrup-55 consumption alters hepatic lipid metabolism and promotes triglyceride accumulation. J Nutr Biochem 39:32–39. https://doi.org/10.1016/j.jnutbio.2016.09.010

    Article  CAS  PubMed  Google Scholar 

  93. Schultz A, Barbosa-da-Silva S, Aguila MB, Mandarim-de-Lacerda CA (2015) Differences and similarities in hepatic lipogenesis, gluconeogenesis and oxidative imbalance in mice fed diets rich in fructose or sucrose. Food Funct 6(5):1684–1691. https://doi.org/10.1039/c5fo00251f

    Article  CAS  PubMed  Google Scholar 

  94. Ackerman Z, Oron-Herman M, Grozovski M, Rosenthal T, Pappo O, Link G, Sela BA (2005) Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension 45(5):1012–1018. https://doi.org/10.1161/01.HYP.0000164570.20420.67

    Article  CAS  PubMed  Google Scholar 

  95. Chiu S, Sievenpiper JL, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ, Ha V, Di Buono M, Jenkins AL, Leiter LA, Wolever TM, Don-Wauchope AC, Beyene J, Kendall CW, Jenkins DJ (2014) Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 68(4):416–423. https://doi.org/10.1038/ejcn.2014.8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Perez-Pozo SE, Schold J, Nakagawa T, Sanchez-Lozada LG, Johnson RJ, Lillo JL (2010) Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond) 34(3):454–461. https://doi.org/10.1038/ijo.2009.259

    Article  CAS  Google Scholar 

  97. Fox IH, Kelley WN (1972) Studies on the mechanism of fructose-induced hyperuricemia in man. Metabolism 21(8):713–721. https://doi.org/10.1016/0026-0495(72)90120-5

    Article  CAS  PubMed  Google Scholar 

  98. Hurtado del Pozo C, Vesperinas-Garcia G, Rubio MA, Corripio-Sanchez R, Torres-Garcia AJ, Obregon MJ, Calvo RM (2011) ChREBP expression in the liver, adipose tissue and differentiated preadipocytes in human obesity. Biochim Biophys Acta 1811(12):1194–1200. https://doi.org/10.1016/j.bbalip.2011.07.016

    Article  CAS  PubMed  Google Scholar 

  99. Petersen KF, Laurent D, Yu C, Cline GW, Shulman GI (2001) Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans. Diabetes 50(6):1263–1268. https://doi.org/10.2337/diabetes.50.6.1263

    Article  CAS  PubMed  Google Scholar 

  100. Softic S, Gupta MK, Wang GX, Fujisaka S, O’Neill BT, Rao TN, Willoughby J, Harbison C, Fitzgerald K, Ilkayeva O, Newgard CB, Cohen DE, Kahn CR (2017) Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest 127(11):4059–4074. https://doi.org/10.1172/JCI94585

    Article  PubMed  PubMed Central  Google Scholar 

  101. Miller C, Yang X, Lu K, Cao J, Herath K, Rosahl TW, Askew R, Pavlovic G, Zhou G, Li C, Akiyama TE (2018) Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects. Am J Physiol Endocrinol Metab. https://doi.org/10.1152/ajpendo.00027.2018

    Article  PubMed  PubMed Central  Google Scholar 

  102. Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, McMahan RH, Abdelmalek MF, Rosen HR, Jackman MR, MacLean PS, Diggle CP, Asipu A, Inaba S, Kosugi T, Sato W, Maruyama S, Sanchez-Lozada LG, Sautin YY, Hill JO, Bonthron DT, Johnson RJ (2013) High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology 58(5):1632–1643. https://doi.org/10.1002/hep.26594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Ishimoto T, Lanaspa MA, Le MT, Garcia GE, Diggle CP, Maclean PS, Jackman MR, Asipu A, Roncal-Jimenez CA, Kosugi T, Rivard CJ, Maruyama S, Rodriguez-Iturbe B, Sanchez-Lozada LG, Bonthron DT, Sautin YY, Johnson RJ (2012) Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci USA 109(11):4320–4325. https://doi.org/10.1073/pnas.1119908109

    Article  PubMed  Google Scholar 

  104. Huard K, Ahn K, Amor P, Beebe DA, Borzilleri KA, Chrunyk BA, Coffey SB, Cong Y, Conn EL, Culp JS, Dowling MS, Gorgoglione MF, Gutierrez JA, Knafels JD, Lachapelle EA, Pandit J, Parris KD, Perez S, Pfefferkorn JA, Price DA, Raymer B, Ross TT, Shavnya A, Smith AC, Subashi TA, Tesz GJ, Thuma BA, Tu M, Weaver JD, Weng Y, Withka JM, Xing G, Magee TV (2017) Discovery of fragment-derived small molecules for in vivo inhibition of ketohexokinase (KHK). J Med Chem 60(18):7835–7849. https://doi.org/10.1021/acs.jmedchem.7b00947

    Article  CAS  PubMed  Google Scholar 

  105. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O’Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS, Nash CRN, Consortium G, Investigators M, Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WH, Hirschhorn JN, Borecki IB, Consortium G (2011) Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLoS Genet 73:e1001324. https://doi.org/10.1371/journal.pgen.1001324

    Article  CAS  Google Scholar 

  106. Seedorf U, Sen-Chowdhry S, Siminovitch KA, Smit JH, Spector TD, Tan W, Teslovich TM, Tukiainen T, Uitterlinden AG, Van der Klauw MM, Vasan RS, Wallace C, Wallaschofski H, Wichmann HE, Willemsen G, Wurtz P, Xu C, Yerges-Armstrong LM, Alcohol Genome-wide Association C, Diabetes Genetics R, Meta-analyses S, Genetic Investigation of Anthropometric Traits C, Global Lipids Genetics C, Genetics of Liver Disease C, International Consortium for Blood P, Meta-analyses of G, Insulin-Related Traits C, Abecasis GR, Ahmadi KR, Boomsma DI, Caulfield M, Cookson WO, van Duijn CM, Froguel P, Matsuda K, McCarthy MI, Meisinger C, Mooser V, Pietilainen KH, Schumann G, Snieder H, Sternberg MJ, Stolk RP, Thomas HC, Thorsteinsdottir U, Uda M, Waeber G, Wareham NJ, Waterworth DM, Watkins H, Whitfield JB, Witteman JC, Wolffenbuttel BH, Fox CS, Ala-Korpela M, Stefansson K, Vollenweider P, Volzke H, Schadt EE, Scott J, Jarvelin MR, Elliott P, Kooner JS (2011) Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nat Genet 43(11):1131–1138. https://doi.org/10.1038/ng.970

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. van der Harst P, Bakker SJ, de Boer RA, Wolffenbuttel BH, Johnson T, Caulfield MJ, Navis G (2010) Replication of the five novel loci for uric acid concentrations and potential mediating mechanisms. Hum Mol Genet 19(2):387–395. https://doi.org/10.1093/hmg/ddp489

    Article  CAS  PubMed  Google Scholar 

  108. Kolz M, Johnson T, Sanna S, Teumer A, Vitart V, Perola M, Mangino M, Albrecht E, Wallace C, Farrall M, Johansson A, Nyholt DR, Aulchenko Y, Beckmann JS, Bergmann S, Bochud M, Brown M, Campbell H, Consortium E, Connell J, Dominiczak A, Homuth G, Lamina C, McCarthy MI, Consortium E, Meitinger T, Mooser V, Munroe P, Nauck M, Peden J, Prokisch H, Salo P, Salomaa V, Samani NJ, Schlessinger D, Uda M, Volker U, Waeber G, Waterworth D, Wang-Sattler R, Wright AF, Adamski J, Whitfield JB, Gyllensten U, Wilson JF, Rudan I, Pramstaller P, Watkins H, Consortium P, Doering A, Wichmann HE, Study K, Spector TD, Peltonen L, Volzke H, Nagaraja R, Vollenweider P, Caulfield M, Wtccc Illig T, Gieger C (2009) Meta-analysis of 28,141 individuals identifies common variants within five new loci that influence uric acid concentrations. PLoS Genet 5(6):e1000504. https://doi.org/10.1371/journal.pgen.1000504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The study in HFI patients was subsidized by the Netherlands Heart Foundation (#2015T042) and Stofwisselkracht. MB received a personal grant from the Diabetes Foundation (#2017.82.004). DT was supported by Colorado Research Partners LLC and National Institutes of Health (R01DK108859).

Author information

Authors and Affiliations

  1. Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands

    Amée M. Buziau & Martijn C.G.J. Brouwers

  2. Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands

    Amée M. Buziau, Casper G. Schalkwijk, Coen D.A. Stehouwer & Martijn C.G.J. Brouwers

  3. Cardiovascular Research Institute Maastricht (CARIM), Maastricht, The Netherlands

    Amée M. Buziau, Casper G. Schalkwijk, Coen D.A. Stehouwer & Martijn C.G.J. Brouwers

  4. Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands

    Coen D.A. Stehouwer

  5. Department of Biology, Boston University, Boston, MA, USA

    Dean R. Tolan

Authors
  1. Amée M. Buziau
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Casper G. Schalkwijk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Coen D.A. Stehouwer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dean R. Tolan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martijn C.G.J. Brouwers
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Dean R. Tolan or Martijn C.G.J. Brouwers.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Buziau, A.M., Schalkwijk, C.G., Stehouwer, C.D. et al. Recent advances in the pathogenesis of hereditary fructose intolerance: implications for its treatment and the understanding of fructose-induced non-alcoholic fatty liver disease. Cell. Mol. Life Sci. 77, 1709–1719 (2020). https://doi.org/10.1007/s00018-019-03348-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-019-03348-2

Keywords

Search

Navigation