High-fructose diet initially promotes increased aortic wall thickness, liver steatosis, and cardiac histopathology deterioration, but does not increase body fat index

  • Dian Handayani
    Department of Nutrition, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Erlinda Febrianingsih
    Department of Nutrition, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Adelya Desi Kurniawati
    Department of Nutrition, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Inggita Kusumastuty
    Department of Nutrition, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Shafira Nurmalitasari
    Department of Nutrition, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Rahma Micho Widyanto
    Department of Nutrition, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Diah Novida Oktaviani
    Department of Nutrition, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Alma Maghfirotun Innayah
    Master Program in Biomedical Sciences, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia.
  • Etik Sulistyowati
    Nutrition Department, Polytechnic of Health, Malang, Indonesia.


Background: Dietary fats and fructose have been responsible for inducing obesity and body tissues damage due to the consequence of metabolic syndrome through several mechanisms. The body fat index (BFI) is one of the anthropometric measures used to detect obesity in rats. This study aims to examine the correlation between high-fat high-fructose diet and liver steatosis cell count, early atherosclerosis characteristics, and BFI in Sprague Dawley Rats.

Design and methods: 
This was an experimental design using 2 groups of 12-weeks-old Sprague Dawley (SD) rats. The control group received a standard diet and tap water beverages for 17 weeks. The intervention group was fed with high-fat diet from modified AIN 93-M and additional 30% fructose drink. We analyzed the foam cell count, aortic wall thickness, cardiac histopathology, and liver steatosis cell count after the sacrifice process.

The rats in the intervention group had a higher aortic wall thickness, liver steatosis, and foam cell count (+125%, p<0.01; +317%, p<0.01 and +165%, p<0.01 respectively) compared to the control group. The intervention group also showed higher mononuclear inflammatory and hypertrophic cell count. A significant positive correlation was found between dietary fructose with premature atherosclerosis by increasing foam cell count (r=0.66) and aortic wall thickness (r=0.68). In addition, 30% dietary fructose increased liver steatosis (r =0.69) and mononuclear inflammatory cardiac cell count (r=0.61). Interestingly, the intervention had no effect on BFI (p>0.5; r=0.13).

Dietary fat and fructose consumption for 17 weeks promote atherosclerosis, liver steatosis, and cardiac histopathology alteration without increasing BFI.


Suzuki K, Jayasena CN, Bloom SR. Obesity and appetite control. Exp Diabetes Res 2012;2012:1–9. DOI: https://doi.org/10.1155/2012/824305

Sladoje DP, Kisić B, Mirić D. The monitoring of protein markers of inflammation and serum lipid concentration in obese subjects with metabolic syndrome. J Med Biochem 2017;36:366–74. DOI: https://doi.org/10.1515/jomb-2017-0009

Csige I, Ujvárosy D, Szabó Z, et al. The impact of obesity on the cardiovascular system. J Diabetes Res 2018;2018:1–12. DOI: https://doi.org/10.1155/2018/3407306

Ahima RS. Metabolic syndrome: a comprehensive textbook. Cham: Springer; 2016. DOI: https://doi.org/10.1007/978-3-319-11251-0

Kucera O, Cervinkova Z. Experimental models of non-alcoholic fatty liver disease in rats. World J Gastroenterol 2014;20:8364. DOI: https://doi.org/10.3748/wjg.v20.i26.8364

Ministry of Health, Republic of Indonesia. Basic Health Research 2018. Jakarta: Ministry of Health Republic of Indonesia; 2018.

WHO. Obesity and overweight. Geneva: World Health Organization; 2020 [cited 2020 Sep 2]. Available from: https://www.who.int/en/news-room/fact-sheets/detail/obesity-and-overweight

WHO. Time to deliver: report of the WHO Independent High-level Commission on Noncommunicable Diseases. Geneva: WHO; 2018. Available from: https://apps.who.int/iris/handle/10665/272710

Bocarsly ME, Powell ES, Avena NM, et al. High-fructose corn syrup causes characteristics of obesity in rats: increased body weight, body fat and triglyceride levels. Pharmacol Biochem Behav 2010;97:101–6. DOI: https://doi.org/10.1016/j.pbb.2010.02.012

Sakakura K, Nakano M, Otsuka F, et al. Pathophysiology of atherosclerosis plaque progression. Hear Lung Circ 2013;22:399–411. DOI: https://doi.org/10.1016/j.hlc.2013.03.001

Ning B, Wang X, Yu Y, et al. High-fructose and high-fat diet-induced insulin resistance enhances atherosclerosis in Watanabe heritable hyperlipidemic rabbits. Nutr Metab (Lond) 2015;12:30. DOI: https://doi.org/10.1186/s12986-015-0024-3

Aeberli I, Hochuli M, Gerber PA, et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care 2013;36:150–6. DOI: https://doi.org/10.2337/dc12-0540

Ding S, Zhang C, Zhang L, et al. Fructose-fed induced metabolic syndrome model in cynomolgus monkeys. J Vet Sci Technol 2017;8:1–10. DOI: https://doi.org/10.4172/2157-7579.1000479

Sahraoui A, Dewachter C, De Medina G, et al. Myocardial structural and biological anomalies induced by high fat diet in Psammomys obesus gerbils. PLoS One 2016;11:e0148117. DOI: https://doi.org/10.1371/journal.pone.0148117

Supranto J. Teknik sampling untuk survei dan eksperimen. Jakarta: Rineka Cipta; 2000.

Reeves PG. Components of the AIN-93 diets as improvements in the AIN-76A diet. J Nutr 1997;127:838S-41. DOI: https://doi.org/10.1093/jn/127.5.838S

Lee JS, Jun DW, Kim EK, et al. Histologic and metabolic derangement in high-fat, high-fructose, and combination diet animal models. Sci World J 2015;2015:1–9. DOI: https://doi.org/10.1155/2015/306326

Handayani D, Chen J, Meyer BJ, et al. Dietary Shiitake mushroom (Lentinus edodes) prevents fat deposition and lowers triglyceride in rats fed a high-fat diet. J Obes 2011;2011:1–8. DOI: https://doi.org/10.1155/2011/258051

Ble-Castillo JL, Aparicio-Trapala MA, Juárez-Rojop IE, et al. Differential effects of high-carbohydrate and high-fat diet composition on metabolic control and insulin resistance in normal rats. Int J Environ Res Public Health 2012;9:1663–76. DOI: https://doi.org/10.3390/ijerph9051663

Pang J, Xi C, Huang X, Cui J, et al. Effects of excess energy intake on glucose and lipid metabolism in C57BL/6 mice. PLoS One 2016;11:e0146675. DOI: https://doi.org/10.1371/journal.pone.0146675

Yang Y, Smith Jr DL, Keating KD, et al. Variations in body weight, food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice. Obesity (Silver Spring) 2014;22:2147–55. DOI: https://doi.org/10.1002/oby.20811

Burchfield JG, Kebede MA, Meoli CC, et al. High dietary fat and sucrose result in an extensive and time-dependent deterioration in health of multiple physiological systems in mice. J Biol Chem 2018;293:5731–45. DOI: https://doi.org/10.1074/jbc.RA117.000808

Wang CY, Liao JK. A mouse model of diet-induced obesity and insulin resistance. Methods Mol Biol 2012;821:421–33. DOI: https://doi.org/10.1007/978-1-61779-430-8_27

Watanabe H, Inaba Y, Kimura K, et al. Dietary mung bean protein reduces hepatic steatosis, fibrosis, and inflammation in male mice with diet-induced, nonalcoholic fatty liver disease. J Nutr 2017;147:52–60. DOI: https://doi.org/10.3945/jn.116.231662

Ullah R, Rauf N, Nabi G, et al. Role of nutrition in the pathogenesis and prevention of non-alcoholic fatty liver disease: recent updates. Int J Biol Sci 2019;15:265. DOI: https://doi.org/10.7150/ijbs.30121

Johnson RJ, Perez-Pozo SE, Sautin YY, et al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev 2009;30:96–116. DOI: https://doi.org/10.1210/er.2008-0033

Johnson AMF, Olefsky JM. The origins and drivers of insulin resistance. Cell 2013;152:673–84. DOI: https://doi.org/10.1016/j.cell.2013.01.041

Dziuba O. Blood coagulation and aortic wall integrity in rats with obesity-induced insulin resistance. Ukr Biochem J 2018;90:14–23. DOI: https://doi.org/10.15407/ubj90.02.014

Yoo S, Ahn H, Park YK. High dietary fructose intake on cardiovascular disease related parameters in growing rats. Nutrients 2016;9:11. DOI: https://doi.org/10.3390/nu9010011

Yuan Y, Zhao L, Chen Y, et al. Advanced glycation end products (AGEs) increase human mesangial foam cell formation by increasing Golgi SCAP glycosylation in vitro. Am J Physiol Physiol 2011;301:F236–43. DOI: https://doi.org/10.1152/ajprenal.00646.2010

Swier VJ, Tang L, Radwan MM, et al. The role of high cholesterol-high fructose diet on coronary arteriosclerosis. Histol Histopathol 2015;31:167–76.

Sakono M, Fukuyama T, Ni W-H, et al. Comparison between dietary soybean protein and casein of the inhibiting effect on atherogenesis in the thoracic aorta of hypercholesterolemic (ExHC) rats treated with experimental hypervitamin D. Biosci Biotechnol Biochem 1997;61:514–9. DOI: https://doi.org/10.1271/bbb.61.514

Darioli R. Dietary Protein and Atherosclerosis. Int J Vitam Nutr Res 2011;81:153. DOI: https://doi.org/10.1024/0300-9831/a000057

Panchal SK, Poudyal H, Iyer A, et al. High-carbohydrate high-fat diet–induced metabolic syndrome and cardiovascular remodeling in rats. J Cardiovasc Pharmacol 2011;57:51–64. DOI: https://doi.org/10.1097/FJC.0b013e3181feb90a

Stansfield WE, Ranek M, Pendse A, Set al. The pathophysiology of cardiac hypertrophy and heart failure. In: Cellular and molecular pathobiology of cardiovascular disease. San Diego: Elsevier; 2014. p. 51-78. DOI: https://doi.org/10.1016/B978-0-12-405206-2.00004-1

Zhang Y-B, Meng Y-H, Chang S, et al. High fructose causes cardiac hypertrophy via mitochondrial signaling pathway. Am J Transl Res 2016;8:4869-80.

Ostrander DB, Sparagna GC, Amoscato AA, et al. Decreased cardiolipin synthesis corresponds with cytochromec release in palmitate-induced cardiomyocyte apoptosis. J Biol Chem 2001;276:38061–7. DOI: https://doi.org/10.1074/jbc.M107067200

Unger RH, Orci L. Lipoapoptosis: its mechanism and its diseases. Biochim Biophys Acta (BBA)-Molecular Cell Biol Lipids 2002;1585:202-12.

Popkin BM, Nielsen SJ. The sweetening of the world’s diet. Obes Res 2003;11:1325–32. DOI: https://doi.org/10.1038/oby.2003.179

Imanningsih N, Jahari AB, Permaesih ID, et al. Consumption and sources of added sugar in Indonesia: a review. Asia Pac J Clin Nutr 2018;27:47.

Lustig RH, Mulligan K, Noworolski SM, Tet al. Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity 2016;24:453–60. DOI: https://doi.org/10.1002/oby.21371