Chronic liquid fructose supplementation does not cause liver tumorigenesis but elicits clear sex differences in the metabolic response in Sprague–Dawley rats

  • Núria Roglans Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain; Institute of Biomedicine, University of Barcelona, Barcelona, Spain; and Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Madrid, Spain
  • Miguel Baena Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
  • Gemma Sangüesa Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain
  • Ana Magdalena Velázquez Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain; and Institute of Biomedicine, University of Barcelona, Barcelona, Spain
  • Christian Griñán-Ferré Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain; and Institute of Neuroscience (UBNeuro), University of Barcelona, Barcelona, Spain
  • Mercè Pallàs Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain; and Institute of Neuroscience (UBNeuro), University of Barcelona, Barcelona, Spain
  • Rosa María Sánchez Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain; Institute of Biomedicine, University of Barcelona, Barcelona, Spain; and Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Madrid, Spain
  • Marta Alegret Department of Pharmacology, Toxicology and Therapeutic Chemistry, School of Pharmacy and Food Science, University of Barcelona, Barcelona, Spain; Institute of Biomedicine, University of Barcelona, Barcelona, Spain; and Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición (CIBERObn), Madrid, Spain
  • Juan Carlos Laguna-Egea University of Barcelona
Keywords: diethyl nitrosamine, hepatocellular cancer, metabolic syndrome, sugar-sweetened beverages, sugary drinks

Abstract

Background: Non-alcoholic fatty liver disease (NAFLD) has increased over the last decades and may evolve into hepatocellular carcinoma (HCC). As HCC is challenging to treat, knowledge on the modifiable risk factors for NAFLD/HCC (e.g. hyper caloric diets rich in fructose) is essential.

Objective and design: We used a model of diethyl nitrosamine-induced hepatocarcinogenesis to investigate the liver cancer-promoting effects of a diet supplemented with 10% liquid fructose, administered to male and female rats for 11 months. A subset of the fructose-supplemented rats received resveratrol (RVT) in the last 4 months of treatment.

Results and discussion: Rat livers showed no de visu or histological evidence of liver tumorigenesis. However, we observed metabolic abnormalities that could be related to cancer development mainly in the female fructose-supplemented rats, such as increases in weight, adiposity and hepatic triglyceride levels, as well as hyperglycaemia, hyperuricemia, hyperleptinemia and a reduced insulin sensitivity index, which were partially reversed by RVT. Therefore, we performed a targeted analysis of 84 cancer-related genes in the female liver samples, which revealed expression changes associated with cancer-related pathways. Analysis of individual genes indicated that some changes increased the risk of hepatocarcinogenesis (Sfrp2Ccl5Socs3, and Gstp1), while others exerted a protective/preventive effect (Bcl2 and Cdh1).

Conclusion: Our data clearly demonstrate that chronic fructose supplementation, as the sole dietary intervention, does not cause HCC development in rats.

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References


  1. Samuel VT, Shulman GI. Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases. Cell Metab 2018; 27(1): 22–41. doi: 10.1016/j.cmet.2017.08.002

  2. Kim GA, Lee HC, Choe J, Kim MJ, Lee MJ, Chang HS, et al. Association between non-alcoholic fatty liver disease and cancer incidence rate. J Hepatol 2018; 68(1): 140–6. doi: 10.1016/j.jhep.2017.09.012

  3. Eso Y, Marusawa H. Novel approaches for molecular targeted therapy against hepatocellular carcinoma. Hepatol Res 2018; 48(8): 597–607. doi: 10.1111/hepr.13181

  4. Saran U, Humar B, Kolly P, Dufour JF. Hepatocellular carcinoma and lifestyles. J Hepatol 2016; 64(1): 203–14. doi: 10.1016/j.jhep.2015.08.028

  5. Laguna JC, Alegret M, Roglans N. Simple sugar intake and hepatocellular carcinoma: epidemiological and mechanistic insight. Nutrients 2014; 6(12): 5933–54. doi: 10.3390/nu6125933

  6. El-Agroudy NN, Kurzbach A, Rodionov RN, O’Sullivan J, Roden M, Birkenfeld AL, et al. Are lifestyle therapies effective for NAFLD treatment? Trends Endocrinol Metab 2019; 30(10): 701–9. doi: 10.1016/j.tem.2019.07.013

  7. Lagiou P, Rossi M, Tzonou A, Georgila C, Trichopoulos D, La Vecchia C. Glycemic load in relation to hepatocellular carcinoma among patients with chronic hepatitis infection. Ann Oncol 2009; 20(10): 1741–5. doi: 10.1093/annonc/mdp059

  8. Rossi M, Lipworth L, Maso LD, Talamini R, Montella M, Polesel J, et al. Dietary glycemic load and hepatocellular carcinoma with or without chronic chronic hepatitis infection. Ann Oncol 2009; 20(10): 1736–40. doi: 10.1093/annonc/mdp058

  9. Fedirko V, Lukanova A, Bamia C, Trichopolou A, Trepo E, Nöthlings U, et al. Glycemic index, glycemic load, dietary carbohydrate, and dietary fiber intake and risk of liver and biliary tract cancers in Western Europeans. Ann Oncol 2013; 24(2): 543–53. doi: 10.1093/annonc/mds434

  10. Stepien M, Duarte-Salles T, Fedirko V, Trichopoulou A, Lagiou P, Bamia C, et al. Consumption of soft drinks and juices and risk of liver and biliary tract cancers in a European cohort. Eur J Nutr 2016; 55(1): 7–20. doi: 10.1007/s00394-014-0818-5

  11. Nomura K, Yamanouchi T. The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease. J Nutr Biochem 2012; 23(3): 203–8. doi: 10.1016/j.jnutbio.2011.09.006

  12. Tasevska N, Park Y, Jiao L, Hollenbeck A, Subar AF, Potischman N. Sugars and risk of mortality in the NIH-AARP Diet and Health Study. Am J Clin Nutr 2014; 99(5): 1077–88. doi: 10.3945/ajcn.113.069369

  13. Kumamoto R, Uto H, Oda K, Ibusuki R, Tanoue S, Arima S, et al. Dietary fructose enhances the incidence of precancerous hepatocytes induced by administration of diethylnitrosamine in rat. Eur J Med Res 2013; 18: 54. doi: 10.1186/2047-783X-18-54

  14. Dowman JK, Hopkins LJ, Reynolds GM, Nikolaou N, Armstrong MJ, Shaw JC, et al. Development of hepatocellular carcinoma in a murine model of nonalcoholic steatohepatitis induced by use of a high-fat/fructose diet and sedentary lifestyle. Am J Pathol 2014; 184(5): 1550–61. doi: 10.1016/j.ajpath.2014.01.034

  15. Healy ME, Chow JDY, Byrne FL, Breen DS, Leitinger N, Li C, et al. Dietary effects on liver tumor burden in mice treated with the hepatocellular carcinogen diethylnitrosamine. J Hepatol 2015; 62(3): 599–606. doi: 10.1016/j.jhep.2014.10.024

  16. Healy ME, Lahiri S, Hargett SR, Chow JDY, Byrne FL, Breen DS, et al. Dietary sugar intake increases liver tumor incidence in female mice. Sci Rep 2016; 6: 1–9. doi: 10.1038/srep22292

  17. Ozawa T, Maehara N, Kai T, Arai S, Miyazaki T. Dietary fructose-induced hepatocellular carcinoma development manifested in mice lacking apoptosis inhibitor of macrophage (AIM). Genes Cells 2016; 21(12): 1320–32. doi: 10.1111/gtc.12446

  18. Goncalves MD, Lu C, Tutnauer J, Hartman TE, Hwang SK, Murphy CJ, et al. High-fructose corn syrup enhances intestinal tumor growth in mice. Science 2019; 363(6433): 1345–9. doi: 10.1126/science.aat8515

  19. Mayes P. Intermediary metabolism of fructose. Am J Clin Nutr 1993; 58: 754S–65S. doi: 10.1093/ajcn/58.5.754S

  20. Pan A, Hu FB. Effects of carbohydrates on satiety: differences between liquid and solid food. Curr Opin Clin Nutr Metab Care 2011; 14: 385–90. doi: 10.1097/MCO.0b013e328346df36

  21. Sengupta P. The Laboratory Rat: Relating Its Age With Human’s. Int J Prev Med. 2013 Jun; 4(6): 624–30. PMID: 23930179; PMCID: PMC3733029.

  22. Herranz D, Muñoz-Martin M, Cañamero M, Mulero F, Martinez-Pastor B, Fernandez-Capetillo O, et al. Sirt1 improves healthy ageing and protects from metabolic syndrome-associated cancer. Nat Commun 2010; 1: 3. doi: 10.1038/ncomms1001

  23. Bitterman JL, Chung JH. Metabolic effects of resveratrol: addressing the controversies. Cell Mol Life Sci 2015; 72(8): 1473–88. doi: 10.1007/s00018-014-1808-8

  24. Lin HC, Chen YF, Hsu WH, Yang CW, Kao CH, Tsai TF. Resveratrol helps recovery from fatty liver and protects against hepatocellular carcinoma induced by hepatitis B virus X protein in a mouse model. Cancer Prev Res 2012; 5(7): 952–62. doi: 10.1158/1940-6207.CAPR-12-0001

  25. Ventura EE, Davis JN, Goran MI. Sugar content of popular sweetened beverages based on objective laboratory analysis: focus on fructose content. Obesity 2011; 19(4): 868–74. doi: 10.1038/oby.2010.255

  26. Sangüesa G, Roglans N, Laguna JC, Alegret M. Liquid fructose and liver insulin signaling: molecular mechanisms controlling hepatic steatosis. Mol Nutr Carbohydrates 2019:149–72. doi: 10.1016/B978-0-12-849886-6.00004-5

  27. Verd JC, Peris C, Alegret M, Díaz C, Hernández G, Vázquez M, et al. Different effect of simvastatin and atorvastatin on key enzymes involved in VLDL synthesis and catabolism in high fat/cholesterol fed rabbits. Br J Pharmacol 1999; 127(6): 1479–85. doi: 10.1038/sj.bjp.0702668

  28. Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 2015; 43(D1): D447–52. doi: 10.1093/nar/gku1003

  29. Huang DW, Sherman BT, Tan Q, Kir J, Liu D, Bryant D, et al. DAVID Bioinformatics resources: expanded annotation database and novel algorithms to better extract biology from large gene lists. Nucleic Acids Res 2007; 35(Suppl 2): 169–75. doi: 10.1093/nar/gkm415

  30. Roglans N, Vilà L, Farré M, Alegret M, Sánchez RM, Vázquez-Carrera M, et al. Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology 2007; 45(3): 778–88. doi: 10.1002/hep.21499

  31. Vilà L, Roglans N, Perna V, Sánchez RM, Vázquez-Carrera M, Alegret M, et al. Liver AMP/ATP ratio and fructokinase expression are related to gender differences in AMPK activity and glucose intolerance in rats ingesting liquid fructose. J Nutr Biochem 2011; 22(8): 741–51. doi: 10.1016/j.jnutbio.2010.06.005

  32. Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, et al. Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 2018; 14(3): 140–62. doi: 10.1038/nrendo.2017.161

  33. Charles River. No title. Available from: https://www.criver.com/products-services/find-model/cd-sd-igs-rat?region=3661[cited 2020 May 18].

  34. Sanguino E, Bejarano R, Alegret M, Sánchez RM, Vázquez-Carrera M, Laguna JC. Sexual dimorphism in lipid metabolic phenotype associated with old age in Sprague-Dawley rats. Exp Gerontol 2004; 39(9): 1295–306. doi: 10.1016/j.exger.2004.06.007

  35. Aldinucci D, Colombatti A. The inflammatory chemokine CCL5 and cancer progression. Mediators Inflamm 2014; 2014: 292376. doi: 10.1155/2014/292376

  36. Radha G, Raghavan SC. BCL2: a promising cancer therapeutic target. Biochim Biophys Acta – Rev Cancer 2017; 1868(1): 309–14. doi: 10.1016/j.bbcan.2017.06.004

  37. Sakai M, Muramatsu M. Regulation of glutathione transferase P: a tumor marker of hepatocarcinogenesis. Biochem Biophys Res Commun 2007; 357(3): 575–8. doi: 10.1016/j.bbrc.2007.03.174

  38. Zhang H, Yu C, Chen M, Li Z, Tian S, Jiang J, et al. miR-522 contributes to cell proliferation of hepatocellular carcinoma by targeting DKK1 and SFRP2. Tumor Biol 2016; 37(8): 11321–9. doi: 10.1007/s13277-016-4995-0

  39. Durham GA, Williams JJL, Nasim MT, Palmer TM. Targeting SOCS proteins to control JAK-STAT signalling in disease. Trends Pharmacol Sci 2019; 40(5): 298–308. doi: 10.1016/j.tips.2019.03.001

  40. Mendonsa AM, Na TY, Gumbiner BM. E-cadherin in contact inhibition and cancer. Oncogene 2018; 37(35): 4769–80. doi: 10.1038/s41388-018-0304-2

Published
2021-09-22
How to Cite
Roglans, N., Baena, M., Sangüesa, G., Velázquez, A. M., Griñán-Ferré, C., Pallàs, M., Sánchez, R. M., Alegret, M., & Laguna-Egea, J. C. (2021). Chronic liquid fructose supplementation does not cause liver tumorigenesis but elicits clear sex differences in the metabolic response in Sprague–Dawley rats. Food & Nutrition Research, 65. https://doi.org/10.29219/fnr.v65.7670
Section
Original Articles