Dietary Fructose-Induced Hepatic Injury in Male and Female Rats: Influence of Resveratrol

Abstract

Purpose: Relatively little is known about gender-dependent susceptibility to hepatic injury induced by nutritional factors. In the current study, we investigated dietary fructose-induced hepatic degeneration and roles of endothelial nitric oxide synthase (eNOS), insulin receptor (IRβ) and substrate-1 (IRS-1) expressions in association with inflammatory markers in male and female rats. Moreover, we examined potential effect of resveratrol on fructose-induced changes.

Methods: Male and female rats were divided into 4 groups as control, resveratrol, fructose and resveratrol plus fructose. All rats were fed with a standard diet with or without resveratrol (500 mg/kg). Fructose was given as 10% in drinking waterfor 24 weeks.

Results: Long-term dietary fructose caused parenchymal degeneration and hyperemia in association with impaired eNOS mRNA/protein expressions in liver of male and female rats. This dietary intervention also led to increases in hepatic triglyceride content, TNFα and IL-1β levels in both genders. Gender-related differences to consequence of fructose consumption were not obvious. Resveratrol supplementation markedly attenuated hepatic degeneration, hyperemia and triglyceride content in association with reduced TNFα and IL-1β levels, but enhanced IRβ mRNA and IRS-1 protein, in male and female rats upon fructose feeding.

Conclusion: Long-term dietary fructose causes hepatic degeneration possibly via a decrease in eNOS, but increase in TNFα and IL-1β, in both genders. Resveratrol supplementation improved fructose-induced hepatic injury.

Key words

fructose - resveratrol - hepatic degeneration - eNOS - IRS-1 - TNFα - IL-1β

• References

• 1 Biddinger SB, Hernandez-Ono A, Rask-Madsen C et al. Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis. Cell Metab 2008; 7: 125-134
• 2 Grant RW, Dixit VD. Mechanisms of disease: inflammasome activation and the development of type 2 diabetes. Front Immunol 2013; 4: 1-10
• 3 Basaranoglu M, Basaranoglu G, Sabuncu T et al. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol 2013; 19: 1166-1172
• 4 Ackerman Z, Oron-Herman M, Grozovski M et al. Fructose-induced fatty liver disease: hepatic effects of blood pressure and plasma triglyceride reduction. Hypertension 2005; 45: 1012-1018
• 5 Armutcu F, Coskun O, Gürel A et al. Thymosin alpha 1 attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats. Clin Biochem 2005; 38: 540-547
• 6 Nomura K, Yamanouchi T. The role of fructose-enriched diets in mechanisms of nonalcoholic fatty liver disease. J Nutr Biochem 2012; 23: 203-208
• 7 Spruss A, Kanuri G, Uebel K et al. Role of the inducible nitric oxide synthase (iNOS) in the onset of fructose-induced steatosis in mice. Antioxid Redox Signal 2011; 14: 2121-2135
• 8 Kanuri G, Spruss A, Wagnerberger S et al. Role of tumor necrosis factor a (TNFα) in the onset of fructose-induced nonalcoholic fatty liver disease in mice. J Nutr Biochem 2011; 22: 527-534
• 9 Veličković N, Djordjevic A, Vasiljević A et al. Tissue-specific regulation of inflammation by macrophage migration inhibitory factor and glucocorticoids in fructose-fed Wistar rats. Br J Nutr 2013; 110: 456-465
• 10 Sadi G, Ergin V, Yilmaz G et al. High-fructose corn syrup-induced hepatic dysfunction in rats: improving effect of resveratrol. Eur J Nutr 2015; 54: 895-904
• 11 Zhao CX, Xu X, Cui Y et al. Increased endothelial nitricoxide synthase expression reduces hypertension and hyperinsulinemia in fructose-treated rats. J Pharmacol Exp Ther 2009; 328: 610-620
• 12 Haas JT, Miao J, Chanda D et al. Hepatic insulin signaling is required for obesity-dependent expression of SREBP-1c mRNA but not for feeding-dependent expression. Cell Metab 2012; 15: 873-884
• 13 Babacanoglu C, Yildirim N, Sadi G et al. Resveratrol prevents high-fructose corn syrup-induced vascular insulin resistance and dysfunction in rats. Food Chem Toxicol 2013; 60: 160-167
• 14 Pektaş MB, Sadi G, Akar F. Long-term dietary fructose causes gender-different metabolic and vascular dysfunction in rats: modulatory effects of resveratrol. Cell Physiol Biochem 2015; 37: 1407-1420
• 15 Xu X, Zhao CX, Wang L et al. Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db/db mice. Diabetes 2010; 59: 997-1005
• 16 Xu X, Tu L, Wang L et al. CYP2J3 gene delivery reduces insulin resistance via upregulation of eNOS in fructose-treated rats. Cardiovasc Diabetol 2011; 10: 114 1-10
• 17 Pektas MB, Koca HB, Sadi G et al. Dietary fructose activates insulin signaling and inflammation in adipose tissue: Modulatory role of resveratrol. BioMed Res Int 2016; 2016: 8014252
• 18 Timmers S, Konings E, Bilet L et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 2011; 14: 612-622
• 19 Spruss A, Henkel J, Kanuri G et al. Female mice are more susceptible to nonalcoholic fatty liver disease: sex-specific regulation of the hepatic AMP-activated protein kinase-plasminogen activator inhibitor 1 cascade, but not the hepatic endotoxin response. Mol Med 2012; 18: 1346-1355
• 20 Sheludiakova A, Rooney K, Boakes RA. Metabolic and behavioural effects of sucrose and fructose/glucose drinks in the rat. Eur J Nutr 2012; 51: 445-454
• 21 Lowry OH, Rosebrough NJ, Farr AL et al. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275
• 22 Kubota N, Kubota T, Itoh S et al. Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding. Cell Metab 2008; 8: 49-64
• 23 Kanuri G, Spruss A, Wagnerberger S et al. Fructose-induced steatosis in mice: role of plasminogen activator inhibitor-1, microsomal triglyceride transfer protein and NKT cells. Lab Invest 2011; 91: 885-895
• 24 González-Rodríguez A, Mas Gutierrez JA, Sanz-González S et al. Inhibition of PTP1B restores IRS1-mediated hepatic insulin signaling in IRS2-deficient mice. Diabetes 2010; 59: 588-599
• 25 Abd El-Haleim EA, Bahgat AK, Saleh S. Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression. World J Gastroenterol 2016; 22: 2931-2948
• 26 Pektaş MB, Sadi G, Koca HB et al. Resveratrol ameliorates the components of hepatic inflammation and apoptosis in a rat model of streptozotocin-induced diabetes. Drug Dev Res 2016; 77: 12-19