Fructose effects in rodent models
In rodent models a high fructose diet induces a “metabolic syndrome” that includes development
of insulin resistance, hypertriglyceridemia, abdominal obesity, hypertension and hepatic
steatosis. For example, in hamsters, a 60% fructose diet for 2 weeks (compared to normal
starch chow) induced hypertriglycerdemia, hyperinsulinemia, whole body insulin resistance and
overproduction of VLDL1. A longer 5 week study demonstrated hepatic macro- and
microvesicular fat with a 200% increase in hepatic triglycerides from fructose-enriched chow
compared to standard rat chow.2 Fructose also appears to induce oxidative stress.3 In animals
consuming a glucose beverage, rats consuming a fructose beverage for one year demonstrated
increased markers of lipid peroxidation.4 Glutathione (GSH) redox (Eh), a measure of oxidative
stress, becomes more oxidized within minutes of a high sucrose meal compared to standard
starch diet in rats.5 The oxidative stress from fructose may not affect all compartments of the
hepatocyte equally. We examined thioredoxin-2 in the mitochondria of hepatocytes in fructoseversus glucose-fed mice.6 Both groups developed hepatic steatosis and significantly decreased
the thioredoxin-2, suggesting that mitochondrial oxidative stress plays a role in the development
of hepatic steatosis. Supporting the role of oxidative stress in the long term effects of fructose
feeding, several studies have shown that treatment with anti-oxidants prevents adverse
metabolic effects of feeding fructose in rodents, implying that the oxidative changes are integral
to the mechanisms of fructose induced steatosis.7-10
Interestingly, treatment with antibiotics prevents many of the effects of fructose. 3, 11 Bergheim et
al fed mice fructose and sucrose and found that fructose fed mice given antibiotics had
markedly less endotoxin in the portal blood and less hepatic steatosis.3 Fructose is
malabsorbed when fed in large amounts because it is taken up in the small intestine through a
saturable, facultative receptor (GLUT5). In animal models, increased intestinal permeability
associated with high fructose feeding leads to endotoxemia and increased secretion of
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inflammatory cytokines, which can lead to insulin resistance and fatty liver.3, 12, 13 Thus, one of
the key mechanisms for fructose effects may be via provision of alternative substrate to gut
flora, resulting in alterations in the microbiome, gut permeability, increased portal endotoxin and
ensuing hepatic inflammation and insulin resistance.11
The hepatic steatosis induced by fructose in animal models is not typically associated with
visible hepatic inflammation or cell injury. However, in models combining excess fructose with a
second insult such as magnesium14, or copper deficiency,15 or a trans fat16 or high-fat diet,17
inflammation has been produced. The combination of fructose and high fat/trans fat is part of
what has been called the “Westernized diet” and reflects the human situation where multiple
nutritional “hazards” can be present simultaneously. Another study demonstrating the complex
conditions that could simulate NASH combined the “Westernized diet” with low vitamin D intake.
This resulted in increased inflammation and insulin resistance.18 Some difficulties arise when
utilizing animal models to understand effects of fructose in human NAFLD because
carbohydrate and lipid metabolism are markedly different in humans and rodents.19 Thus, it is
important that mechanistic findings of fructose be replicated in humans where possible.
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Ackerman Z, Oron-Herman M, Rosenthal M, Pappo O, Link G, Sela B. Fructose-induced fatty liver
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Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, McClain CJ, Bischoff SC.
Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of
endotoxin. J Hepatol 2008;48:983-92.
Levi B, Werman MJ. Long-term fructose consumption accelerates glycation and several agerelated variables in male rats. J Nutr 1998;128:1442-9.
Blouet C, Mariotti F, Azzout-Marniche D, Mathe V, Mikogami T, Tome D, Huneau J. Dietary
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stress in fructose-induced Fatty liver is not caused by sulfur amino Acid insufficiency. Nutrients
2011;3:987-1002.
Son D, Hutchings S, Pang C. Chronic N-acetylcysteine prevents fructose-induced insulin
resistance in rats. European Journal of Pharmacology 2005;508:205-210.
Thirunavukkarasu V, Anuradha C. Influence of alpha-lipoic acid on lipid peroxidation and
antioxidant defence system in blood of insulin-resistant rats. Diabetes, Obesity and Metabolism
2004;6:200-207.
Armutcu F, Coskun O, Gurel A, Kanter M, Can M, Ucar F, Unalacak M. Thymosin alpha 1
attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats. Clin
Biochem 2005;38:540-7.
Diniz Y, Rocha K, Souza G, Galhardi C, Ebaid G, Rodrigues H, Filho J, Cicogna A, Novelli E. Effects
of N-acetylcysteine on sucrose-rich diet-induced hyperglycaemia dyslipidemia and oxidative
stress in rats. Eur J Pharmacol 2006;543:151-157.
Vos MB, McClain CJ. Fructose takes a toll. Hepatology 2009;50:1004-6.
Kanuri G, Spruss A, Wagnerberger S, Bischoff SC, Bergheim I. Role of tumor necrosis factor alpha
(TNFalpha) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. J Nutr
Biochem;22:527-34.
Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll-like receptor 4 is
involved in the development of fructose-induced hepatic steatosis in mice. Hepatology
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Rayssiguier Y, Gueux E, Nowacki W, Rock E, Mazur A. High fructose consumption combined with
low dietary magnesium intake may increase the incidence of the metabolic syndrome by
inducing inflammation. Magnes Res 2006;19:237-43.
Song M, Schuschke DA, Zhou Z, Chen T, Pierce WM, Jr., Wang R, et al. High fructose feeding
induces copper deficiency in Sprague-Dawley rats: A novel mechanism for obesity related fatty
liver. J Hepatol 2012;56:433-40.
Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with
hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup
equivalent. Am J Physiol Gastrointest Liver Physiol 2008;295:G987-95.
Charlton M, Krishnan A, Viker K, Sanderson S, Cazanave S, McConico A, Masuoko H, Gores G.
Fast food diet mouse: novel small animal model of NASH with ballooning, progressive fibrosis,
and high physiological fidelity to the human condition. Am J Physiol Gastrointest Liver Physiol
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Roth CL, Elfers CT, Figlewicz DP, Melhorn SJ, Morton GJ, Hoofnagle A, et al. Vitamin D deficiency
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