Chronic consumption of fructose in combination with trans fatty acids but not with saturated fatty acids induces nonalcoholic steatohepatitis with fibrosis in rats
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Consumption of Western diet high in fat and fructose has been attributed to the recent epidemic of nonalcoholic fatty liver disease (NAFLD). However, the impact of specific fatty acids on the progression of NAFLD to nonalcoholic steatohepatitis (NASH) is poorly understood. In the present study, we investigated the chronic effects of consumption of fructose in combination with saturated fatty acids (SFA) or trans fatty acids (TFA) on the development of NAFLD.
Male Sprague–Dawley rats were randomly assigned to six isocaloric starch/high fructose (44% of calories), high fat (39% calories) diet containing either starch–peanut oil, fructose–peanut oil, fructose–palmolein, fructose–clarified butter, fructose–coconut oil or fructose–partially hydrogenated vegetable oil and fed for 24 weeks. Palmolein, clarified butter and coconut oil were used as the source of SFA whereas partially hydrogenated vegetable oil was used as the source of TFA. Peanut oil was used as the reference oil.
Long-term feeding of fructose in combination with SFA or TFA induced hepatic steatosis of similar extent associated with upregulation of stearoyl CoA desaturase-1. In contrast, fructose in combination with TFA induced NASH with fibrosis as evidenced by upregulation of hepatic proinflammatory cytokine and fibrogenic gene expression, increased hepatic oxidative stress and adipocytokine imbalance. Histopathological analysis revealed the presence of NASH with fibrosis. Further, peanut oil prevented the development of NAFLD in fructose-fed rats.
Fructose in combination with TFA caused NASH with fibrosis by inducing oxidative stress and inflammation, whereas, fructose in combination with SFA caused simple steatosis, suggesting that the type of fatty acid is more important for the progression of NAFLD.
KeywordsWestern diet High fructose High fat Saturated fatty acids Trans fatty acids Inflammation Oxidative stress Gene expression Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis Fibrosis
- ACC α
Acetyl CoA carboxylase alpha
Area under the curve
Carbohydrate responsive element binding protein
- CPT 1
Carnitine palmotyl tranferase 1
Enzyme linked immunosorbent assay
Fatty acid methyl ester
Fatty acid synthase
Fructose–partially hydrogenated vegetable oil
Hematoxylin and eosin
Homeostasis model assessment-insulin resistance
Hepatic stellate cells
Intraperitoneal glucose tolerance test
Nonalcoholic fatty liver disease
NAFLD Activity score
Plasminogen activator inhibitor-1
Polymerase chain reaction
Partially hydrogenated vegetable oil
- PPAR α
Peroxisome proliferator-activated receptor alpha
- PPAR γ
Peroxisome proliferator-activated receptor gamma
Stearoyl CoA desaturase-1
Saturated fatty acid
- SREBP 1c
Sterol regulatory element binding protein 1c
Thiobarbituric acid reactive substances
Trans fatty acid
- TNF α
Tumor necrosis factor alpha
This study was funded by Grants in aid (5/4/3-7/TF/2011/NCD-II) from Indian Council of Medical Research, Government of India to AI. JS was supported by a fellowship from Indian Council of Medical Research, Government of India.
AI and JS designed the study, analyzed the data and wrote the manuscript. JS, AS, KSR and VSS conducted the animal experiment and prepared the experimental diets. PUK and MVS carried out histopathological analysis of liver and NAS scoring. SG and JS involved in mRNA expression studies by RT-qPCR. JS, KSR and CM carried out biochemical estimations. All the authors read and approved the manuscript.
Compliance with ethical standards
Conflict of interest
All the authors declare no conflict of interest.
- 7.Mohan V, Farooq S, Deepa M, Ravikumar R, Pitchumoni CS (2009) Prevalence of non-alcoholic fatty liver disease in urban south Indians in relation to different grades of glucose intolerance and metabolic syndrome. Diabetes Res Clin Pract 84:84–91. doi: 10.1016/j.diabres.2008.11.039 CrossRefPubMedGoogle Scholar
- 17.Sakamuri A, Pitla S, Putcha UK, Jayapal S, Pothana S et al (2016) Transient decrease in circulatory testosterone and homocysteine precedes the development of metabolic syndrome features in fructose-fed Sprague Dawley rats. J Nutr Metab 2016:7510840. doi: 10.1155/2016/7510840 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA (2008) Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 295:G987–G995. doi: 10.1152/ajpgi.90272.2008 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Huang LL, Wan JB, Wang B, He CW, Ma H et al (2013) Suppression of acute ethanol-induced hepatic steatosis by docosahexaenoic acid is associated with downregulation of stearoyl-CoA desaturase 1 and inflammatory cytokines. Prostaglandins Leukot Essent Fatty Acids 88:347–353. doi: 10.1016/j.plefa.2013.02.002 CrossRefPubMedGoogle Scholar
- 39.Schindhelm RK, Diamant M, Dekker JM, Tushuizen ME, Teerlink T et al (2006) Alanine aminotransferase as a marker of non-alcoholic fatty liver disease in relation to type 2 diabetes mellitus and cardiovascular disease. Diabetes Metab Res Rev 22:437–443. doi: 10.1002/dmrr.666 CrossRefPubMedGoogle Scholar
- 44.Dentin R, Girard J, Postic C (2005) Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c): two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87:81–86. doi: 10.1016/j.biochi.2004.11.008 CrossRefPubMedGoogle Scholar
- 47.Miyazaki M, Dobrzyn A, Man WC, Chu K, Sampath H et al (2004) 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 279:25164–25171. doi: 10.1074/jbc.M402781200 CrossRefPubMedGoogle Scholar
- 49.Sellmann C, Priebs J, Landmann M, Degen C, Engstler AJ et al (2015) Diets rich in fructose, fat or fructose and fat alter intestinal barrier function and lead to the development of nonalcoholic fatty liver disease over time. J Nutr Biochem 26:1183–1192. doi: 10.1016/j.jnutbio.2015.05.011 CrossRefPubMedGoogle Scholar
- 51.Pierce AA, Duwaerts CC, Soon RK, Siao K, Grenert JP et al (2016) Isocaloric manipulation of macronutrients within a high-carbohydrate/moderate-fat diet induces unique effects on hepatic lipogenesis, steatosis and liver injury. J Nutr Biochem 29:12–20. doi: 10.1016/j.jnutbio.2015.10.020 CrossRefPubMedGoogle Scholar
- 52.de Souza RJ, Mente A, Maroleanu A, Cozma AI, Ha V, Kishibe T, Uleryk E, Budylowski P, Schünemann H, Beyene J, Anand SS (2015) Intake of saturated and trans unsaturated fatty acids and risk of all-cause mortality, cardiovascular disease, and type 2 diabetes: systematic review and meta-analysis of observational studies. BMJ 351:h3978. doi: 10.1136/bmj.h3978 CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Bugianesi E, Pagotto U, Manini R, Vanni E, Gastaldelli A et al (2005) Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J Clin Endocrinol Metab 90:3498–3504. doi: 10.1210/jc.2004-2240 CrossRefPubMedGoogle Scholar
- 67.Ma F, Li P, Zhang Q, Yu L, Zhang L (2015) Rapid determination of trans-resveratrol in vegetable oils using magnetic hydrophilic multi-walled carbon nanotubes as adsorbents followed by liquid chromatography-tandem mass spectrometry. Food Chem 178:259–266. doi: 10.1016/j.foodchem.2015.01.021 CrossRefPubMedGoogle Scholar