Mediators of Inflammation

Mediators of Inflammation / 2012 / Article

Research Article | Open Access

Volume 2012 |Article ID 601032 |

Cassiano Felippe Gonçalves de Albuquerque, Patrícia Burth, Mauricio Younes Ibrahim, Diogo Gomes Garcia, Patrícia Torres Bozza, Hugo Caire Castro Faria Neto, Mauro Velho Castro Faria, "Reduced Plasma Nonesterified Fatty Acid Levels and the Advent of an Acute Lung Injury in Mice after Intravenous or Enteral Oleic Acid Administration", Mediators of Inflammation, vol. 2012, Article ID 601032, 8 pages, 2012.

Reduced Plasma Nonesterified Fatty Acid Levels and the Advent of an Acute Lung Injury in Mice after Intravenous or Enteral Oleic Acid Administration

Academic Editor: Giamila Fantuzzi
Received26 Sep 2011
Revised12 Nov 2011
Accepted13 Nov 2011
Published27 Feb 2012


Although exerting valuable functions in living organisms, nonesterified fatty acids (NEFAs) can be toxic to cells. Increased blood concentration of oleic acid (OLA) and other fatty acids is detected in many pathological conditions. In sepsis and leptospirosis, high plasma levels of NEFA and low albumin concentrations are correlated to the disease severity. Surprisingly, 24 h after intravenous or intragastric administration of OLA, main NEFA levels (OLA inclusive) were dose dependently decreased. However, lung injury was detected in intravenously treated mice, and highest dose killed all mice. When administered by the enteral route, OLA was not toxic in any tested conditions. Results indicate that OLA has important regulatory properties on fatty acid metabolism, possibly lowering circulating fatty acid through activation of peroxisome proliferator-activated receptors. The significant reduction in blood NEFA levels detected after OLA enteral administration can contribute to the already known health benefits brought about by unsaturated-fatty-acid-enriched diets.

1. Introduction

Nonesterified fatty acids (NEFAs) are transported by the blood stream bound to albumin, a condition avoiding their cytotoxicity [1, 2]. Besides being an important fuel for the energetic metabolism, they also modulate leukocyte function, acting as signaling molecules [35]. Several cell types exhibit morphological features of apoptosis and necrosis after NEFA exposure [6, 7]. Oleic (OLA) and linoleic acids activate caspases 3 and 6, enhancing the generation of reactive oxygen species and a significant mitochondrial depolarization in leukocytes [8, 9].

Symptom severity in diseases as sepsis, leptospirosis, and pancreatitis is associated to increased serum NEFA [1013]. Severe leptospirosis and sepsis are also characterized by a concomitant decrease in plasma albumin concentration consequent to a functional liver injury or increased vascular permeability possibly caused by NEFA toxicity [1315]. Accordingly, increased OLA and decreased albumin plasma levels seem to predict the development of acute respiratory distress syndrome (ARDS) [16, 17]. Since OLA and other nonesterified unsaturated fatty acids are potent Na/K-ATPase inhibitors, whether in vitro [18, 19] or in vivo [20], the involvement of the lung Na/K pump inhibition in the advent of ARDS has to be considered. In experimental animals, intravenous OLA injection can induce acute lung injury (ALI) [21, 22]. This syndrome is characterized by neutrophil infiltration and edema formation [23], due to increased endothelial permeability and loss of epithelial barrier function [24], causing neutrophil and macrophage accumulation in the lung. Upon activation, these cells produce inflammatory mediators [25]. Lipid bodies (lipid-rich inclusions found in the leukocyte cytosol) are also augmented in ALI [26]. They act as amplifiers of inflammatory lipid mediator production such as prostaglandin E2 (PGE2) in macrophages and leukotriene B4 (LTB4) in macrophages and neutrophils [27]. In the present work, such parameters were used to characterize the onset of ALI after intravenous oleic acid administration.

On the other hand, many reports highlight the association of unsaturated fatty acid diets to a healthy lifestyle. The well-known Mediterranean diet contains large amounts of olive oil, which is rich in the esterified form of OLA [28]. Furthermore, dietary monounsaturated fatty acids were considered protective against metabolic syndrome and cardiovascular disease risks [29]. Populations using such diets have reduced serum triglycerides and lower incidence of cardiovascular problems [30, 31].

The present study aimed at a better understanding of some deleterious and putative beneficial effects of OLA, when directly administered to mice. We investigated the consequences of increasing OLA doses, administered by intravenous or intragastric routes, on plasma NEFA concentration and on the triggering of an acute lung injury.

2. Material and Methods

2.1. Animals

All experiments were conducted on male Swiss mice weighting 3 3 ± 3  g obtained from the Oswaldo Cruz Foundation breeding unit. Animals were lodged at 22°C with a 12 h light/dark cycle and free access to food and water. Animal housing conditions and all experimental procedures conformed to institutional regulations and were in accordance with the National Institute of Health guidelines on animal care. All procedures described here were approved by the Institutional Animal Welfare Committee under license number 002-08.

2.2. Preparation of Tris-Oleate Solutions

Oleic acid obtained from Sigma Chemicals was used to prepare a 100 mmol/L tris-oleate solution. After weighting and water addition, tris powder (Trisma base-Sigma) was slowly added until the pH reached 10.0. The mixture was sonicated for complete tris-oleate solubility and then the pH was carefully adjusted to 7.6 with diluted HCl. Working oleate solutions were prepared by appropriate dilutions of the 100 mmol/L solution with phosphate buffered saline (PBS) pH 7.6.

2.3. Intravenous Administration of Oleate

Intravenous injections were performed into the orbital plexus (inner angle of the eye ball), and blood was collected by cardiac puncture 24 h latter. In some experiments, blood samples were collected 6 after the injection. Control groups received 100 μL of saline. Other groups received 100 μL of tris-oleate solutions corresponding to oleate doses of 20, 40, 80, and 160 mg/kg.

2.4. Intragastric Administration of Oleate

A thin catheter coupled to a 1.0 mL syringe was introduced through the mouse esophagus and 100 μL of the appropriate oleate solution or PBS (control animals) were injected into the gastric lumen. Oleate doses of 20, 40, 80, and 160 mg/kg were also used. Blood was collected by cardiac puncture 24 h latter.

2.5. Plasma NEFA Quantification

Plasma concentrations of the predominant NEFA—palmitic, oleic, linoleic, palmitoleic, and stearic acids—were determined by high performance liquid chromatography (HPLC) as described by Puttman et al. [32]. Methodological details were delineated in a previous publication [13].

2.6. Albumin Quantification

Plasma albumin concentration was determined by the colorimetric procedure of Doumas et al. [33] using bovine serum albumin solutions as standards.

2.7. Total and Differential Cell Analysis on Bronchoalveolar Lavage Fluid (BALF)

The bronchoalveolar lavage was performed after isolating the trachea by blunt dissection. A small caliber tube was inserted and secured in the airway. PBS (1.0 mL) was then instilled and gently aspirated. This procedure was repeated three times, and collected fluids were pooled. In every instillation/aspiration cycle, the same volume (1.0 mL) was recovered from each animal. Total leukocyte counts were performed by light microscopy in Neubauer chambers after diluting BALF samples in Türk’s solution (2% acetic acid). Differential leukocyte counts were determined in cytocentrifuged smears stained by the May-Grunwald-Giemsa method. Total BALF protein was determined by the Micron BCA Kit method (Pierce) according to the manufacturer’s instructions.

2.8. Lipid Body Staining and Counting

While still moist, leukocytes on cytospin slides were fixed in 3.7% formaldehyde in Ca2+, Mg2+-free Hank’s balanced salt solution (HBSS), pH 7.4 and stained with 1.5% OsO4 as described in Bozza et al. [34]. Lipid bodies were counted by light microscopy with oil immersion objective lens in 50 consecutively scanned leukocytes.

2.9. PGE2 and LTB4 Assays

LTB4 and PGE2 in BALF supernatants were assayed by ELISA kits according to the manufacturer’s instructions (Cayman Chemical, Ann Arbor, MI).

2.10. Statistical Analysis

Results were expressed as mean ± SEM and were analyzed by the Neuman-Keuls-Student test. Differences were considered significant when 𝑃 < 0 . 0 5 .

3. Results

When mice were intravenously injected with increasing OLA doses (20, 40 and 80 mg/kg), a dose-dependent decrease in plasma NEFA concentrations especially oleic, linoleic and palmitic acids (Figure 1(a)), and total fatty acids (Figure 1(b)) were observed 24 h after the injection. To define if this effect could be detected at an earlier moment, we performed an experiment evaluating NEFA concentrations 6 h after OLA injection, using the 80 mg/kg OLA dose (this dose corresponded to the maximal response obtained in the experiment of Figure 1(a)). Results for this early-time point (Figure 1(c)) showed only minor decreases relative to controls in some NEFA concentrations which were not statistically significant. Albumin levels were only slightly altered (Table 1).

OLA dose (mg/kg)

Albumin (μM) I.V. OLA 325±20.0 nd
Albumin (μM) I.G. OLA 367.3±12.1

Nd: not determined.
Results are mean ± SEM of 6 to 7 different experiments.

In order to characterize the onset of ALI, we measured in BALF samples the following parameters: protein extravasation, leukocyte accumulation, lipid body formation in leukocytes and PGE2 and LTB4 production, which were used as markers of lung edema and inflammation. Although OLA is potentially able to induce lung injury, intravenously injected OLA in 20 and 40 mg/kg doses did not induce BALF cell migration or did not produce modifications on protein BALF content (Figure 2). Notwithstanding, 24 h after the 80 mg/kg dose, an infiltration of mononuclear cells and neutrophils, as well as an augmented total BALF protein, was detected. LTB4 was also significantly increased 6 h after this challenge (Figure 2). Lipid bodies in BALF leukocytes and the lipid mediator PGE2 in BALF supernatant (Figure 3) were also considerably augmented 24 h after this same OLA challenge. A dose of 160 mg/kg killed all mice. These animals presented early signs of severe lung injury and died within 10 minutes after injections.

When the same OLA doses were administered to mice by the enteral route, lowered individual and total NEFA concentrations were also detected (Figures 4(a) and 4(b), resp.). This decrease was substantially more pronounced than the one seen in intravenously treated animals. Lung injury was not found even in the highest dose tested as can be seen in Figure 5. Since lung edema and leukocyte infiltration were not detected in this experiment, assays for inflammatory mediators were not performed.

4. Discussion

Herein we demonstrated an unexpected decrease in NEFA plasma levels after intravenous or enteral OLA administration. In this regard, several studies have shown that fatty acids can regulate its own metabolism, acting at gene transcription level. Some transcription factors are prospective fatty acid targets regulating the expression of enzymes involved in lipid metabolism [3538]. Nonesterified fatty acid availability is sensed by peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors controlling fatty acid storage, degradation, and adipocyte differentiation [39, 40]. Although in the present study we did not test OLA binding to PPAR, this fatty acid was already reported so effective as polyunsaturated fatty acids in PPARα binding and activation [41] and was also a PPARγ ligand [42]. In fact, PPARα activation in the liver stimulates the transcription of carnitine palmitoil-transferase 1 (CPT1) and uncoupling protein 1, leading to increased fatty acid degradation [43]. Fish oils contain PPARα activators that, similarly to hypolipidemic drugs, decreased triglyceride synthesis and increased mitochondrial fatty acid β-oxidation [44]. PPARγ activation augmented fatty acid clearance by the adipose tissue and hepatocytes, consequently decreasing their plasma concentrations [45]. Hence, PPAR activation seems to be an important condition decreasing nonesterified fatty acid blood concentrations. In this way, PPARγ agonists lowered plasmatic NEFA concentration [45] while PPARα agonists led to a similar effect by increasing NEFA oxidation [46].

Mice receiving OLA through the intravenous route (80 mg/kg) already presented signals of lung injury, characterized by increased protein extravasation, cell migration and cell activation with increased lipid body formation and PGE2 release. Moreover, LTB4, a potent neutrophil chemotactic molecule [47], was augmented at an early stage, thus contributing for neutrophil migration. In our conditions, OLA lung toxicity can be explained by the rapid arrival of albumin unbound-OLA in the lung capillary net. It is important to note that this amount of OLA, if diluted in the whole mouse blood (considered as 2.5 mL), would give a concentration of at least 4000 μmol/L, which is around 1.7 and 6.6 times the control levels of total fatty acid and OLA, respectively. Surely, during the few seconds of traveling from the injection point to lung, OLA concentration would be much higher than 4000 μmol/L. Moreover, a 160 mg/kg intravenous dose killed all animals within 10 min after injections, a toxic effect certainly due to albumin unbound-OLA. In this context, it was proposed that the toxicity of intravenously administered OLA could be diminished by a concomitant albumin injection [48].

OLA enteral administration was not toxic in any tested doses. Since an appreciable part of OLA undergoes esterification during the intestinal absorptive mechanism and considering that intestinal absorption is a much slower process, an increase in albumin unbound-OLA is prevented in this condition. It is worth of note that OLA administration by the gastric route (40–80 mg/kg) was twice as much efficient in lowering total plasma NEFA (a decrease of about 60%) than the intravenous administration (around 30%). At this point, we would like to emphasize published data showing that mice consuming olive oil-enriched diet (thus an OLA enriched-diet) had increased survival after a LPS induced-shock [49]. This shock is characteristically seen in sepsis, a disease coursing with high plasma NEFA concentrations. In this case, diet-induced-reduced-plasma NEFA could be an explanation for the extended mice survival.

There are evident differences in OLA distribution in the body when this fatty acid is administered by intravenous or enteral routes. In intravenously treated animals, OLA is rapidly and significantly trapped in the lung microvasculature causing lung inflammation. After enteral administration, OLA is mostly esterified and transported through the abdominal lymphatic system then reaching the venous system, heart, lung and, afterwards, is distributed to the whole organism. The enteral route follows, thus, the normal physiologic mechanisms of lipid absorption and transport.

Other nonesterified fatty acids may have similar effects on NEFA plasma levels. In this work, OLA was chosen because not only toxic but also benefic effects of this fatty acid are well documented in the literature.

5. Conclusions

In conclusion, OLA seems to participate in the regulation of fatty acid metabolism. Intravenous OLA administration (40 mg per kg of body weight) lowered plasma NEFA concentrations, but higher doses were toxic, leading to lung injury or killing the animals. On the other side, our results suggest a benefic effect of low doses of orally administered OLA (about 40 to 80 mg per kg of body weight) in reducing plasma NEFA concentrations of normal animals. This finding sum up the other benefits brought about by the ingestion of diets containing OLA-enriched fat, particularly olive oil.


ALI: Acute lung injury
ARDS: Acute respiratory distress syndrome
BALF: Bronchoalveolar lavage fluid
CPT1: Carnitine palmitoil-transferase 1
NEFA: Nonesterified fatty acids
HPLC: High performance liquid chromatography
IL: Interleukin
LTB4: Leukotriene B4
IV: Intravenous
IG: Intragastric
LNA: Linoleic acid (18 : 2n-6)
OLA: Oleic acid (18 : 1n-9)
PGE2: Prostaglandin E2
PPAR: Peroxisome proliferator-activated receptors
TNF: Tumor necrosis factor.


This work received financial supports from Fundação de Amparo a Pesquisa do Estado do Rio de Janeiro (FAPERJ), Grants E-26/111.636/2008 and E-26/111.024/2008, Programa Estratégico de Apoio à Pesquisa em Saúde (PAPES) FIOCRUZ, and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). The authors acknowledge the following institutions where this work was accomplished: Universidade do Estado do Rio de Janeiro (UERJ), Fundação Oswaldo Cruz (FIOCRUZ) e Universidade Federal Fluminense (UFF). They thank Dr. Emely Kazan for the skilled help in performing the chromatographic work.


  1. G. J. van der Vusse, “Albumin as fatty acid transporter,” Drug Metabolism and Pharmacokinetics, vol. 24, no. 4, pp. 300–307, 2009. View at: Publisher Site | Google Scholar
  2. J. M. Weinberg, “Lipotoxicity,” Kidney International, vol. 70, no. 9, pp. 1560–1566, 2006. View at: Publisher Site | Google Scholar
  3. T. Martins De Lima, R. Gorjão, E. Hatanaka et al., “Mechanisms by which fatty acids regulate leucocyte function,” Clinical Science, vol. 113, no. 1-2, pp. 65–77, 2007. View at: Publisher Site | Google Scholar
  4. S. Costanzi, S. Neumann, and M. C. Gershengorn, “Seven transmembrane-spanning receptors for free fatty acids as therapeutic targets for diabetes mellitus: pharmacological, phylogenetic, and drug discovery aspects,” Journal of Biological Chemistry, vol. 283, no. 24, pp. 16269–16273, 2008. View at: Publisher Site | Google Scholar
  5. P. Yaqoob and P. C. Calder, “Fatty acids and immune function: new insights into mechanisms,” British Journal of Nutrition, vol. 98, no. 1, pp. S41–S45, 2007. View at: Publisher Site | Google Scholar
  6. M. Artwohl, A. Lindenmair, M. Roden et al., “Fatty acids induce apoptosis in human smooth muscle cells depending on chain length, saturation, and duration of exposure,” Atherosclerosis, vol. 202, no. 2, pp. 351–362, 2009. View at: Publisher Site | Google Scholar
  7. P. Rockenfeller, J. Ring, V. Muschett et al., “Fatty acids trigger mitochondrion-dependent necrosis,” Cell Cycle, vol. 9, no. 14, pp. 2836–2842, 2010. View at: Publisher Site | Google Scholar
  8. D. A. Healy, R. W. G. Watson, and P. Newsholme, “Polyunsaturated and monounsaturated fatty acids increase neutral lipid accumulation, caspase activation and apoptosis in a neutrophil-like, differentiated hl-60 cell line,” Clinical Science, vol. 104, no. 2, pp. 171–179, 2003. View at: Publisher Site | Google Scholar
  9. T. Martins De Lima, M. F. Cury-Boaventura, G. Giannocco, M. T. Nunes, and R. Curi, “Comparative toxicity of fatty acids on a macrophage cell line (J774),” Clinical Science, vol. 111, no. 5, pp. 307–317, 2006. View at: Publisher Site | Google Scholar
  10. H. R. Rosen and H. Tuchler, “Pulmonary injury in acute experimental pancreatitis correlates with elevated levels of free fatty acids in rats,” HPB Surgery, vol. 6, no. 2, pp. 79–90, 1992. View at: Google Scholar
  11. K. Sztefko and J. Panek, “Serum free fatty acid concentration in patients with acute pancreatitis,” Pancreatology, vol. 1, no. 3, pp. 230–236, 2001. View at: Publisher Site | Google Scholar
  12. A. C. Nogueira, V. Kawabata, P. Biselli et al., “Changes in plasma free fatty acid levels in septic patients are associated with cardiac damage and reduction in heart rate variability,” Shock, vol. 29, no. 3, pp. 342–348, 2008. View at: Publisher Site | Google Scholar
  13. P. Burth, M. Younes-Ibrahim, M. C. B. Santos, H. C. Castro-Faria Neto, and M. V. De Castro Faria, “Role of nonesterified unsaturated fatty acids in the pathophysiological processes of leptospiral infection,” Journal of Infectious Diseases, vol. 191, no. 1, pp. 51–57, 2005. View at: Publisher Site | Google Scholar
  14. A. Fleck, G. Raines, and F. Hawker, “Increased vascular permeability: a major cause of hypoalbuminaemia in disease and injury,” The Lancet, vol. 1, no. 8432, pp. 781–784, 1985. View at: Google Scholar
  15. B. Ruot, D. Breuillé, F. Rambourdin, G. Bayle, P. Capitan, and C. Obled, “Synthesis rate of plasma albumin is a good indicator of liver albumin synthesis in sepsis,” American Journal of Physiology, vol. 279, no. 2, pp. E244–E251, 2000. View at: Google Scholar
  16. A. T. Hostmark, “Serum fatty acid/albumin molar ratio and the risk of diseases,” Medical Hypotheses, vol. 44, no. 6, pp. 539–541, 1995. View at: Publisher Site | Google Scholar
  17. S. L. Bursten, D. A. Federighi, P. E. Parsons et al., “An increase in serum C18 unsaturated free fatty acids as a predictor of the development of acute respiratory distress syndrome,” Critical Care Medicine, vol. 24, no. 7, pp. 1129–1136, 1996. View at: Publisher Site | Google Scholar
  18. M. Younes-Ibrahim, P. Burth, M. V. Castro Faria et al., “Inhibition of Na,K-ATPase by an endotoxin extracted from Leptospira interrogans: a possible mechanism for the physiopathology of leptospirosis,” Comptes Rendus de l'Academie des Sciences, vol. 318, no. 5, pp. 619–625, 1995. View at: Google Scholar
  19. M. Younes-Ibrahim, B. Buffin-Meyer, L. Cheval et al., “Na,K-ATPase: a molecular target for Leptospira interrogans endotoxin,” Brazilian Journal of Medical and Biological Research, vol. 30, no. 2, pp. 213–223, 1997. View at: Google Scholar
  20. I. Vadász, R. E. Morty, A. Olschewski et al., “Thrombin impairs alveolar fluid clearance by promoting endocytosis of Na+,K+-ATPase,” American Journal of Respiratory Cell and Molecular Biology, vol. 33, no. 4, pp. 343–354, 2005. View at: Publisher Site | Google Scholar
  21. K. G. Davidson, A. D. Bersten, H. A. Barr, K. D. Dowling, T. E. Nicholas, and I. R. Doyle, “Lung function, permeability, and surfactant composition in oleic acid-induced acute lung injury in rats,” American Journal of Physiology, vol. 279, no. 6, pp. L1091–L1102, 2000. View at: Google Scholar
  22. G. Beilman, “Pathogenesis of oleic acid-induced lung injury in the rat: distribution of oleic acid during injury and early endothelial cell changes,” Lipids, vol. 30, no. 9, pp. 817–823, 1995. View at: Publisher Site | Google Scholar
  23. C. L. Guimarães, P. G. Trentin, and G. A. Rae, “Endothelin ETB receptor-mediated mechanisms involved in oleic acid-induced acute lung injury in mice,” Clinical Science, vol. 103, supplement 48, pp. 340S–344S, 2002. View at: Google Scholar
  24. L. B. Ware and M. A. Matthay, “The acute respiratory distress syndrome,” New England Journal of Medicine, vol. 342, no. 18, pp. 1334–1349, 2000. View at: Publisher Site | Google Scholar
  25. M. A. Matthay and G. A. Zimmerman, “Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management,” American Journal of Respiratory Cell and Molecular Biology, vol. 33, no. 4, pp. 319–327, 2005. View at: Publisher Site | Google Scholar
  26. P. T. Bozza, K. G. Magalhães, and P. F. Weller, “Leukocyte lipid bodies—Biogenesis and functions in inflammation,” Biochimica et Biophysica Acta, vol. 1791, no. 6, pp. 540–551, 2009. View at: Publisher Site | Google Scholar
  27. P. T. Bozza and J. P. B. Viola, “Lipid droplets in inflammation and cancer,” Prostaglandins Leukotrienes and Essential Fatty Acids, vol. 82, no. 4-6, pp. 243–250, 2010. View at: Publisher Site | Google Scholar
  28. P. M. Kris-Etherton, “AHA science advisory. monounsaturated fatty acids and risk of cardiovascular disease. American Heart Association. Nutrition Committee,” Circulation, vol. 100, no. 11, pp. 1253–1258, 1999. View at: Google Scholar
  29. L. G. Gillingham, S. Harris-Janz, and P. J. H. Jones, “Dietary monounsaturated fatty acids are protective against metabolic syndrome and cardiovascular disease risk factors,” Lipids, vol. 46, no. 3, pp. 209–228, 2011. View at: Publisher Site | Google Scholar
  30. W. C. Willett, F. Sacks, A. Trichopoulou et al., “Mediterranean diet pyramid: a cultural model for healthy eating,” American Journal of Clinical Nutrition, vol. 61, no. 6, pp. 3277–3288, 1995. View at: Google Scholar
  31. D. Richard, P. Bausero, C. Schneider, and F. Visioli, “Polyunsaturated fatty acids and cardiovascular disease,” Cellular and Molecular Life Sciences, vol. 66, no. 20, pp. 3277–3288, 2009. View at: Publisher Site | Google Scholar
  32. M. Puttmann, H. Krug, E. Von Ochsenstein, and R. Kattermann, “Fast HPLC determination of serum free fatty acids in the picomole range,” Clinical Chemistry, vol. 39, no. 5, pp. 825–832, 1993. View at: Google Scholar
  33. B. T. Doumas, W. Ard Watson, and H. G. Biggs, “Albumin standards and the measurement of serum albumin with bromcresol green,” Clinica Chimica Acta, vol. 31, no. 1, pp. 87–96, 1971. View at: Google Scholar
  34. P. T. Bozza, J. L. Payne, S. G. Morham, R. Langenbach, O. Smithies, and P. F. Weller, “Leukocyte lipid body formation and eicosanoid generation: cyclooxygenase-independent inhibition by aspirin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 93, no. 20, pp. 11091–11096, 1996. View at: Publisher Site | Google Scholar
  35. H. Sampath and J. M. Ntambi, “Polyunsaturated fatty acid regulation of genes of lipid metabolism,” Annual Review of Nutrition, vol. 25, pp. 317–340, 2005. View at: Publisher Site | Google Scholar
  36. D. B. Jump, D. Botolin, Y. Wang, J. Xu, B. Christian, and O. Demeure, “Fatty acid regulation of hepatic gene transcription,” Journal of Nutrition, vol. 135, no. 11, pp. 2503–2506, 2005. View at: Google Scholar
  37. R. Verlengia, R. Gorjão, C. C. Kanunfre et al., “Genes regulated by arachidonic and oleic acids in raji cells,” Lipids, vol. 38, no. 11, pp. 1157–1165, 2003. View at: Publisher Site | Google Scholar
  38. D. B. Jump, S. D. Clarke, A. Thelen, and M. Liimatta, “Coordinate regulation of glycolytic and lipogenic gene expression by polyunsaturated fatty acids,” Journal of Lipid Research, vol. 35, no. 6, pp. 1076–1084, 1994. View at: Google Scholar
  39. M. P. Wymann and R. Schneiter, “Lipid signalling in disease,” Nature Reviews Molecular Cell Biology, vol. 9, no. 2, pp. 162–176, 2008. View at: Publisher Site | Google Scholar
  40. M. C. Cho, K. Lee, S. G. Paik, and D. Y. Yoon, “Peroxisome proliferators-activated receptor (PPAR) modulators and metabolic disorders,” PPAR Research, vol. 2008, Article ID 679137, 14 pages, 2008. View at: Publisher Site | Google Scholar
  41. H. E. Xu, M. H. Lambert, V. G. Montana et al., “Molecular recognition of fatty acids by peroxisome proliferator- activated receptors,” Molecular Cell, vol. 3, no. 3, pp. 397–403, 1999. View at: Publisher Site | Google Scholar
  42. B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999. View at: Google Scholar
  43. T. C. Leone, C. J. Weinheimer, and D. P. Kelly, “A critical role for the peroxisome proliferator-activated receptor α (PPARα) in the cellular fasting response: the PPARα-null mouse as a model of fatty acid oxidation disorders,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 13, pp. 7473–7478, 1999. View at: Publisher Site | Google Scholar
  44. R. K. Berge, L. Madsen, H. Vaagenes, K. J. Tronstad, M. Göttlicher, and A. C. Rustan, “In contrast with docosahexaenoic acid, eicosapentaenoic acid and hypolipidaemic derivatives decrease hepatic synthesis and secretion of triacylglycerol by decreased diacylglycerol acyltransferase activity and stimulation of fatty acid oxidation,” Biochemical Journal, vol. 343, no. 1, pp. 191–197, 1999. View at: Publisher Site | Google Scholar
  45. N. D. Oakes, S. Camilleri, S. M. Furler, D. J. Chisholm, and E. W. Kraegen, “The insulin sensitizer, BRL 49653, reduces systemic fatty acid supply and utilization and tissue lipid availability in the rat,” Metabolism, vol. 46, no. 8, pp. 935–942, 1997. View at: Publisher Site | Google Scholar
  46. D. M. Muoio, J. M. Way, C. J. Tanner et al., “Peroxisome proliferator-activated receptor-α regulates fatty acid utilization in primary human skeletal muscle cells,” Diabetes, vol. 51, no. 4, pp. 901–909, 2002. View at: Google Scholar
  47. B. Samuelsson, S. E. Dahlen, and J. A. Lindgren, “Leukotrienes and lipoxins: structures, biosynthesis, and biological effects,” Science, vol. 237, no. 4819, pp. 1171–1176, 1987. View at: Google Scholar
  48. A. Bezman-Tarcher, “Method for continuous intravenous infusion of large amounts of oleic acid into rats,” Journal of Lipid Research, vol. 10, no. 2, pp. 197–206, 1969. View at: Google Scholar
  49. M. S. Leite, P. Pacheco, R. N. Gomes et al., “Mechanisms of increased survival after lipopolysaccharide-induced endotoxic shock in mice consuming olive oil-enriched diet,” Shock, vol. 23, no. 2, pp. 173–178, 2005. View at: Publisher Site | Google Scholar

Copyright © 2012 Cassiano Felippe Gonçalves de Albuquerque et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

More related articles

 PDF Download Citation Citation
 Download other formatsMore
 Order printed copiesOrder

Related articles

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.