Grasas y Aceites, Vol 67, No 2 (2016)

Extra virgin olive oil reduces liver oxidative stress and tissue depletion of long-chain polyunsaturated fatty acids produced by a high saturated fat diet in mice

R. Valenzuela
Nutrition Department, Faculty of Medicine, Universidad de Chile - Lipid Center, Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Chile

M. C. Hernandez-Rodas
Nutrition Department, Faculty of Medicine, Universidad de Chile, Chile

A. Espinosa
Medical Technology Department, Faculty of Medicine, Chile

M. A. Rincón
Lipid Center, Institute of Nutrition and Food Technology (INTA), Universidad de Chile, Chile

N. Romero
Faculty of Chemical Sciences and Pharmacy, Department of Food Science and Chemical Technology, Universidad de Chile, Chile

C. Barrera
Nutrition Department, Faculty of Medicine, Universidad de Chile, Chile

M. Marambio
Nutrition Department, Faculty of Medicine, Universidad de Chile, Chile

J. Vivero
Nutrition Department, Faculty of Medicine, Universidad de Chile, Chile

A. Valenzuela
Medical Technology Department, Faculty of Medicine - Lipid Center, Institute of Nutrition and Food Technology (INTA), Universidad de Chile - Faculty of Medicine, Universidad de Los Andes, Chile


Long-chain polyunsaturated fatty acids (LCPUFA) which are synthesized mainly in the liver have relevant functions in the organism. A diet high in fat (HFD) generates an increase in the levels of fat and induces oxidative stress (lipo-peroxidation) in the liver, along with a reduction in tissue n-3 and n-6 LCPUFA. Extra virgin olive oil (EVOO) is rich in anti-oxidants (polyphenols and tocopherols) which help to prevent the development of oxidative stress. This study evaluated the role of EVOO in preventing the induction of fat deposition and oxidative stress in the liver and in the depletion of LCPUFA in the liver, erythrocytes and brain generated by a HFD in C57BL/6J mice. Four experimental groups (n = 10/group) were fed a control diet (CD) or a HFD for 12 weeks and were respectively supplemented with EVOO (100 mg/day). The group fed HFD showed a significant increase (p < 0.05) in fat accumulation and oxidative stress in the liver, accompanied by a reduction in the levels of n-3 and n-6 LCPUFA in the liver, erythrocytes and brain. Supplementation with EVOO mitigated the increase in fat and oxidative stress produced by HFD in the liver, along with a normalization of LCPUFA levels in the liver, erythrocytes and brain. It is proposed that EVOO supplementation protects against fat accumulation, and oxidative stress and normalizes n-3 and n-6 LCPUFA depletion induced in mice fed a HFD.


Extra virgin olive oil; High fat diet; Liver fat deposition; Oxidative stress; Tissue n-6 and n-3 LCPUFA depletion

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Bazinet RP and Layé S. 2014. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat. Rev. Neurosci. 15, 771–785. PMid:25387473

Brenna JT, Salem N Jr., Sinclair AJ, Cunnane SC; International Society for the Study of Fatty Acids and Lipids, ISSFAL. 2009. alpha-Linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. Prostaglandins Leukot Essent Fatty Acids. 80, 85–91. PMid:19269799

Bligh EG and Dyer WJ. 1959. A rapid method of total lipid extraction and purification. Can. J. Biochem. Physiol. 37, 911–917. PMid:13671378

Carlson SE. 2009. Docosahexaenoic acid supplementation in pregnancy and lactation. Am. J. Clin. Nutr. 89, 678S-684S. PMid:19116324 PMCid:PMC2647754

Cheng L, Yu Y, Szabo A, Wu Y, Wang H, Camer D, Huang XF. 2015. Palmitic acid induces central leptin resistance and impairs hepatic glucose and lipid metabolism in male mice. J. Nutr. Biochem. 26, 541–548. PMid:25724108

Cicerale S, Lucas LJ, Keast RS. 2012. Antimicrobial, antioxidant and anti-inflammatory phenolic activities in extra virgin olive oil. Curr. Opin. Biotechnol. 23, 129–135. PMid:22000808

De Caterina R. 2011. n-3 fatty acids in cardiovascular disease. N. Engl. J. Med. 364, 2439–2450. PMid:21696310

Mozaffarian D and Wu J. 2012. (n-3) fatty acids and cardiovascular health: are effects of EPA and DHA shared or complementary? J. Nutr. 142, 614S-625S. PMid:22279134 PMCid:PMC3278271

Domenichiello AF, Kitson AP, Bazinet RP. 2015. Is docosahexaenoic acid synthesis from ?-linolenic acid sufficient to supply the adult brain?. Prog. Lipid Res. 59, 54–66. PMid:25920364

Domenichiello AF, Chen CT, Trepanier MO, Stavro PM, Bazinet RP. 2014. Whole body synthesis rates of DHA from ?-linolenic acid are greater than brain DHA accretion and uptake rates in adult rats. J. Lipid Res. 55, 62–74. PMid:24212299 PMCid:PMC3927474

Gerster H. 1998. Can adults adequately convert alpha-linolenic acid (18:3n-3) to eicosapentaenoic acid (20:5n-3) and docosahexaenoic acid (22:6n-3)? Int. J. Vitam. Nutr. 68, 159–173.

Gibson RA, Muhlhausler B, Makrides M. 2011. Conversion of linoleic acid and alpha-linolenic acid to long-chain polyunsaturated fatty acids (LCPUFAs), with a focus on pregnancy, lactation and the first 2 years of life. Matern Child Nutr. 7, 17–26. PMid:21366864

Guillou H, Zadravec D, Martin PG, Jacobsson A. 2010. The key roles of elongases and desaturases in mammalian fatty acid metabolism: Insights from transgenic mice. Prog. Lipid Res. 49, 186–199. PMid:20018209

Haeiwa H, Fujita T, Saitoh Y, Miwa N. 2014. Oleic acid promotes adaptability against oxidative stress in 3T3-L1 cells through lipohormesis. Mol Cell Biochem. 386, 73–83. PMid:24234346

Kwan HY, Niu X, Dai W, Tong T, Chao X, Su T, Chan CL, Lee KC, Fu X, Yi H, Yu H, Li T, Tse AK, Fong WF, Pan SY, Lu A, Yu ZL. 2015. Lipidomic-based investigation into the regulatory effect of Schisandrin B on palmitic acid level in non-alcoholic steatotic livers. Sci. Rep. 5, 9114. PMid:25766252 PMCid:PMC4358044

Li J, Huang M, Shen X. 2014. The association of oxidative stress and pro-inflammatory cytokines in diabetic patients with hyperglycemic crisis. J. Diabetes Complications. 28, 662– 666. PMid:25044235

Li H, Min Q, Ouyang C, Lee J, He C, Zou MH, Xie Z. 2014. AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response. Biochim. Biophys. Acta. 1842, 1844–1854. PMid:25016145

Lim JH, Gerhart-Hines Z, Dominy JE, Lee Y, Kim S, Tabata M, Xiang YK, Puigserver P. 2013. Oleic acid stimulates complete oxidation of fatty acids through protein kinase A-dependent activation of SIRT1-PGC1? complex. J. Biol. Chem. 288, 7117–7126. PMid:23329830 PMCid:PMC3591621

Lin LE, Chen CT, Hildebrand KD, Liu Z, Hopperton KE, Bazinet RP. 2015. Chronic dietary n-6 PUFA deprivation leads to conservation of arachidonic acid and more rapid loss of DHA in rat brain phospholipids. J. Lipid Res. 56, 390–402. PMid:25477531 PMCid:PMC4306692

Lu Y, Cheng J, Chen L, Li C, Chen G, Gui L, Shen B, Zhang Q. Endoplasmic reticulum stress involved in high-fat diet and palmitic acid-induced vascular damages and fenofibrate intervention. Biochem. Biophys. Res. Commun. 458, 1–7. PMid:25592967

Marseglia L, Manti S, D'Angelo G, Nicotera A, Parisi E, Di Rosa G, Gitto E, Arrigo T. 2014. Oxidative stress in obesity: a critical component in human diseases. Int. J. Mol Sci. 16, 378–400. PMid:25548896 PMCid:PMC4307252

Morrison WR and Smith LM. 1964. Preparation of fatty acid methyl esters and dimethylacetals from lipids with boron fluoride-methanol. J. Lipid Res. 5, 600–608. PMid:14221106

Nakamura MT and Nara TY. 2003. Essential fatty acid synthesis and its regulation in mammals. Prostaglandins Leukot Essent Fatty Acids. 68, 145–150.

Nakamura MT and Nara TY. 2004. Structure, function, and dietary regulation of delta 6, delta 5, and delta9 desaturases. Annu. Rev. Nutr. 24, 345–376. PMid:15189125

Nissar AU, Sharma A, Tasduq SA. 2015. Palmitic acid induced lipotoxicity is associated with altered lipid metabolism, enhanced CYP450 2E1 and intracellular calcium mediated ER stress in human hepatoma cells. Toxicol. Res. 4, 1344–1358.

Orr SK, Palumbo S, Bosetti F, Mount HT, Kang JX, Greenwood CE, Ma DW, Serhan CN, Bazinet RP. 2013. Unesterified docosahexaenoic acid is protective in neuroinflammation. J. Neurochem. 127, 78–93. PMid:23919613 PMCid:PMC4068707

Pardo V, González-Rodríguez Á, Muntané J, Kozma SC, Valverde ÁM. 2015. Role of hepatocyte S6K1 in palmitic acid-induced endoplasmic reticulum stress, lipotoxicity, insulin resistance and in oleic acid-induced protection. Food Chem. Toxicol. 80, 298–309. PMid:25846498

Pawlak M, Lefebvre P, Staels B. 2015. Molecular mechanism of PPAR? action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 62, 720–33. PMid:25450203

Rahman I, Kode A, Biswas SK. 2006. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat. Protoc. 1, 3159–3165. PMid:17406579

Reddy KK, Vidya Rajan VK, Gupta A, Aparoy P, Reddanna P. 2015. Exploration of binding site pattern in arachidonic acid metabolizing enzymes, Cyclooxygenases and Lipoxygenases. BMC Res. Notes. 8, 152–162. PMid:25886468 PMCid:PMC4416244

Ruiz-Gutierrez V, Cert A, Rios JJ. 1992. Determination of phospholipid fatty acid and triacylglycerol composition of rat caecal mucosa. J. Chromatogr. 575, 1–6.

Simopoulos AP. 2008. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp. Biol. Med. (Maywood). 233, 674–688. PMid:18408140

Simopoulos AP. 2011. Importance of the omega-6/omega-3 balance in health and disease: evolutionary aspects of diet. World Rev. Nutr. Diet. 102, 10–21. PMid:21865815

Tapia G, Valenzuela R, Espinosa A, Romanque P, Dossi C, Gonzalez-Ma-án D, Videla LA, D'Espessailles A. 2014. N-3 long-chain PUFA supplementation prevents high fat diet induced mouse liver steatosis and inflammation in relation to PPAR-? upregulation and NF-?B DNA binding abrogation. Mol. Nutr. Food Res. 58, 1333–1341. PMid:24436018

Valenzuela A. 2009. Docosahexaenoic acid (DHA), an essential fatty acid for the proper functioning of neuronal cells: Their role in mood disorders. Grasas Aceites. 60, 203–212.

Valenzuela R and Videla LA. 2011. The importance of the long-chain polyunsaturated fatty acid n-6/n-3 ratio in development of non-alcoholic fatty liver associated with obesity. Food Funct. 2, 644–8. PMid:22008843

Valenzuela R, Espinosa A, González-Ma-án D, D'Espessailles A, Fernández V, Videla LA, Tapia G. 2012. N-3 long-chain polyunsaturated fatty acid supplementation significantly reduces liver oxidative stress in high fat induced steatosis. PLoS One. 7, e46400. PMid:23082120 PMCid:PMC3474802

Valenzuela R, Gormáz JG, Masson L, Vizcarra M, Cornejo P, Valenzuela A, Tapia G. 2012. Evaluation of the hepatic bioconversion of ?-linoleic acid (ALA) to eicosapentaenoic acid (EPA) and docosahexahenoic acid (DHA) in rats fed with oils from chia (Salvia hispanica) or rosa mosqueta (Rosa rubiginosa). Grasas Aceites. 63, 61–69.

Valenzuela B R, Barrera R C, González-Astorga M, Sanhueza C J, Valenzuela B A. 2014. Alpha linolenic acid (ALA) from Rosa canina, sacha inchi and chia oils may increase ALA accretion and its conversion into n-3 LCPUFA in diverse tissues of the rat. Food Funct. 5, 1564–1572. PMid:24855655

Valenzuela R, Barrera C, Espinosa A, Llanos P, Orellana P, Videla LA. 2015. Reduction in the desaturation capacity of the liver in mice subjected to high fat diet: Relation to LCPUFA depletion in liver and extrahepatic tissues. Prostaglandins Leukot Essent Fatty Acids. 98, 7–14. PMid:25910408

Videla LA, Rodrigo R, Orellana M, Fernandez V, Tapia G, Qui-ones L, Varela N, Contreras J, Lazarte R, Csendes A, Rojas J, Maluenda F, Burdiles P, Diaz JC, Smok G, Thielemann L, Poniachik J. 2004. Oxidative stress-related parameters in the liver of non-alcoholic fatty liver disease patients. Clin. Sci. (Lond). 106, 261–268. PMid:14556645

Videla LA, Rodrigo R, Araya J, Poniachik J. 2006. Insulin resistance and oxidative stress interdependency in non-alcoholic fatty liver disease. Trends Mol. Med. 12, 555–558. PMid:17049925

Videla LA, Tapia G, Rodrigo R, Pettinelli P, Haim D, Santiba-ez C, Araya AV, Smok G, Csendes A, Gutierrez L, Rojas J, Castillo J, Korn O, Maluenda F, Díaz JC, Rencoret G, Poniachik J. 2009. Liver NF-kappaB and AP-1 DNA binding in obese patients. Obesity (Silver Spring). 17, 973–979. PMid:19165171

Visioli F, Caruso D, Grande S, Bosisio R, Villa M, Galli G, Sirtori C, Galli C. 2005. Virgin Olive Oil Study (VOLOS): vasoprotective potential of extra virgin olive oil in mildly dyslipidemic patients. Eur. J. Nutr. 44, 121–127. PMid:15309433

Zhu L, Liu Z, Feng Z, Hao J, Shen W, Li X, Sun L, Sharman E, Wang Y, Wertz K, Weber P, Shi X, Liu J. 2010. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J. Nutr. Biochem. 21, 1089–1098. PMid:20149621

Zrelli H, Matsuoka M, Kitazaki S, Zarrouk M, Miyazaki H. 2011. Hydroxytyrosol reduces intracellular reactive oxygen species levels in vascular endothelial cells by upregulating catalase expression through the AMPK-FOXO3a pathway. Eur J Pharmacol. 660, 275–282 PMid:21497591

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