Fructose-enriched diet affects hepatic lipid metabolism in young male and female rats in different ways
Keywords:dietary fructose, lipid metabolism, liver, rat, sex differences
Abstract: An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we tested the hypothesis that the effects of fructose overconsumption on hepatic lipid metabolism differ between sexes. To that end we examined the effects of a high-fructose diet on the expression of key enzymes and transcription factors involved in the regulation of fatty acid oxidation and de novo lipogenesis in the liver of 12-week-old male and female Wistar rats. Immediately after weaning, the rats were subjected to a standard diet and 10% fructose solution or drinking water for 9 weeks. The fructose-enriched diet induced hypertriglyceridemia and increased hepatic de novo lipogenesis in both sexes, without lipid deposition in the liver. At the same time, visceral adiposity was observed only in female rats, while in males the treatment stimulated hepatic fatty acid oxidation. The fructose-enriched diet induced sex-specific effects on hepatic lipid metabolism in young rats. These results imply that male and female rats employ different strategies to cope with dietary fructose-related energy overload and to avoid lipid accumulation in the liver.
Received: March 6, 2019; Revised: April 2, 2019; Accepted: April 2, 2019; Published online: April 9, 2019
How to cite this article: Brkljačić J, Veličković N, Elaković I, Teofilović A, Vojnović-Milutinović D, Đorđević A, Matić G. Fructose-enriched diet affects hepatic lipid metabolism in young male and female rats in different ways. Arch Biol Sci. 2019;71(3):417-24.
Jegatheesan P, De Bandt JP. Fructose and NAFLD: The Multifaceted Aspects of Fructose Metabolism. Nutrients. 2017;9(3):230.
Dekker MJ, Su Q, Baker C, Rutledge AC, Adeli K. Fructose: a highly lipogenic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic syndrome. Am J Physiol Endocrinol Metab. 2010;299(5):E685-94.
Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, Sánchez-Lozada LG. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007;86(4):899-906.
Rippe JM, Angelopoulos TJ. Relationship between Added Sugars Consumption and Chronic Disease Risk Factors: Current Understanding. Nutrients. 2016;8(11):E697.
Lowndes J, Sinnett SS, Rippe JM. No Effect of Added Sugar Consumed at Median American Intake Level on Glucose Tolerance or Insulin Resistance. Nutrients. 2015;7(10):8830-45.
Evans RA, Frese M, Romero J, Cunningham JH, Mills KE. Chronic fructose substitution for glucose or sucrose in food or beverages has little effect on fasting blood glucose, insulin, or triglycerides: a systematic review and meta-analysis. Am J Clin Nutr. 2017;106(2):519-29.
Dupas J, Feray A, Goanvec C, Guernec A, Samson N, Bougaran P, Guerrero F, Mansourati J. Metabolic Syndrome and Hypertension Resulting from Fructose Enriched Diet in Wistar Rats. Biomed Res Int. 2017;2017:2494067.
Kawasaki T, Igarashi K, Koeda T, Sugimoto K, Nakagawa K, Hayashi S, Yamaji R, Inui H, Fukusato T, Yamanouchi T. Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis. J Nutr. 2009;139(11):2067-71.
Crescenzo R, Bianco F, Coppola P, Mazzoli A, Valiante S, Liverini G, Iossa S. Adipose tissue remodeling in rats exhibiting fructose-induced obesity. Eur J Nutr. 2014;53(2):413-9.
Miyazaki M, Dobrzyn A, Man WC, Chu K, Sampath H, Kim HJ, Ntambi JM. Stearoyl-CoA desaturase 1 gene expression is necessary for fructose-mediated induction of lipogenic gene expression by sterol regulatory element-binding protein-1c-dependent and -independent mechanisms. J Biol Chem. 2004;279(24):25164-71.
Rebollo A, Roglans N, Baena M, Sanchez RM, Merlos M, Alegret M, Laguna JC. Liquid fructose downregulates Sirt1 expression and activity and impairs the oxidation of fatty acids in rat and human liver cells. Biochim Biophys Acta. 2014;1841(4):514-24.
Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res. 2009;48(1):1-26.
Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000;20(5):1868-76.
Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC, Jr., Kelly DP. Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. Cell Metab. 2006;4(3):199-210.
Rochlani Y, Pothineni NV, Mehta JL. Metabolic Syndrome: Does it Differ Between Women and Men? Cardiovasc Drugs Ther. 2015;29(4):329-38.
Galipeau D, Verma S, McNeill JH. Female rats are protected against fructose-induced changes in metabolism and blood pressure. American journal of physiology Heart and circulatory physiology. 2002;283(6):H2478-84.
Stoppeler S, Palmes D, Fehr M, Holzen JP, Zibert A, Siaj R, Schmidt HH, Spiegel HU, Bahde R. Gender and strain-specific differences in the development of steatosis in rats. Lab Anim. 2013;47(1):43-52.
Ramdhave AS, Ojha S, Nandave M. Energy intake correlates with the levels of fatty acid synthase and insulin-like growth factor-1 in male and female C57BL/6 mice. Am J Transl Res. 2017;9(3):830-44.
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.
Nestorov J, Glban AM, Mijuskovic A, Nikolic-Kokic A, Elakovic I, Velickovic N, Matic G. Long-term fructose-enriched diet introduced immediately after weaning does not induce oxidative stress in the rat liver. Nutr Res. 2014;34(7):646-52.
Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226(1):497-509.
Fletcher MJ. A colorimetric method for estimating serum triglycerides. Clin Chim Acta. 1968;22(3):393-7.
Duncombe WG. The Colorimetric Micro-Determination of Non-Esterified Fatty Acids in Plasma. Clin Chim Acta. 1964;9:122-5.
Vasiljevic A, Velickovic N, Bursac B, Djordjevic A, Milutinovic DV, Nestorovic N, Matic G. Enhanced prereceptor glucocorticoid metabolism and lipogenesis impair insulin signaling in the liver of fructose-fed rats. J Nutr Biochem. 2013;24(11):1790-7.
de Moura RF, Ribeiro C, de Oliveira JA, Stevanato E, de Mello MA. Metabolic syndrome signs in Wistar rats submitted to different high-fructose ingestion protocols. Br J Nutr. 2009;101(8):1178-84.
Janevski M, Ratnayake S, Siljanovski S, McGlynn MA, Cameron-Smith D, Lewandowski P. Fructose containing sugars modulate mRNA of lipogenic genes ACC and FAS and protein levels of transcription factors ChREBP and SREBP1c with no effect on body weight or liver fat. Food Funct. 2012;3(2):141-9.
Vila L, Roglans N, Perna V, Sanchez RM, Vazquez-Carrera M, Alegret M, Laguna JC. 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.
Mahmoud AA, Elshazly SM. Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats. PLoS One. 2014;9(9):e106993.
Ge CX, Yu R, Xu MX, Li PQ, Fan CY, Li JM, Kong LD. Betaine prevented fructose-induced NAFLD by regulating LXRalpha/PPARalpha pathway and alleviating ER stress in rats. Eur J Pharmacol. 2016;770:154-64.
Roglans N, Vila L, Farre M, Alegret M, Sanchez RM, Vazquez-Carrera M, Laguna JC. Impairment of hepatic Stat-3 activation and reduction of PPARalpha activity in fructose-fed rats. Hepatology. 2007;45(3):778-88.
Oosterveer MH, Grefhorst A, van Dijk TH, Havinga R, Staels B, Kuipers F, Groen AK, Reijngoud DJ. Fenofibrate simultaneously induces hepatic fatty acid oxidation, synthesis, and elongation in mice. J Biol Chem. 2009;284(49):34036-44.
Yan F, Wang Q, Xu C, Cao M, Zhou X, Wang T, Yu C, Jing F, Chen W, Gao L, Zhao J. Peroxisome proliferator-activated receptor alpha activation induces hepatic steatosis, suggesting an adverse effect. PLoS One. 2014;9(6):e99245.
Bursac BN, Djordjevic AD, Vasiljevic AD, Vojnovic Milutinovic D, Velickovic NA, Nestorovic NM, Matic GM. Fructose consumption enhances glucocorticoid action in rat visceral adipose tissue. J Nutr Biochem. 2013;24(6):1166-72.
Unger RH, Clark GO, Scherer PE, Orci L. Lipid homeostasis, lipotoxicity and the metabolic syndrome. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2010;1801(3):209-14.
Kovacevic S, Nestorov J, Matic G, Elakovic I. Dietary fructose-related adiposity and glucocorticoid receptor function in visceral adipose tissue of female rats. Eur J Nutr. 2014;53(6):1409-20.