ABSTRACT
Elevated saturated free fatty acid levels during over-nutrition lead to hypothalamic inflammation, which perturbs energy homeostasis. Whether brain-derived metabolites are coupled to the development of obesity pathogenesis during the early over-nutrition period has not been thoroughly investigated. In this study, we found increased linoleic acid, an unsaturated fatty acid, in both the whole brain and hypothalamus of mice fed a high-fat diet for 4 weeks. Furthermore, we observed that linoleic acid effectively reversed the inflammatory responses induced by palmitic acid treatment in microglial cells. Collectively, this study suggests the reversible function of linoleic acid on brain inflammation in association with microglial activation during short-term exposure to a high-fat diet.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Diet, High-Fat/adverse effects , Encephalitis/drug therapy , Linoleic Acid/therapeutic use , Microglia/drug effects , Animals , Anti-Inflammatory Agents/immunology , Encephalitis/etiology , Encephalitis/immunology , Linoleic Acid/immunology , Mice, Inbred C57BL , Microglia/immunology , Palmitic Acid/adverse effects , Palmitic Acid/immunologyABSTRACT
α1-Antitrypsin (A1AT) purified from human plasma upregulates expression and release of angiopoietin-like protein 4 (Angptl4) in adherent human blood monocytes and in human lung microvascular endothelial cells, providing a mechanism for the broad immune-regulatory properties of A1AT independent of its antiprotease activity. In this study, we demonstrate that A1AT (Prolastin), a potent inducer of Angptl4, contains significant quantities of the fatty acids (FA) linoleic acid (C18:2) and oleic acid (C18:1). However, only trace amounts of FAs were present in preparations that failed to increase Angplt4 expression, for example, A1AT (Zemaira) or M-type A1AT purified by affinity chromatography. FA pull-down assays with Western blot analysis revealed a FA-binding ability of A1AT. In human blood-adherent monocytes, A1AT-FA conjugates upregulated expression of Angptl4 (54.9-fold, p < 0.001), FA-binding protein 4 (FABP4) (11.4-fold, p < 0.001), and, to a lesser degree, FA translocase (CD36) (3.1-fold, p < 0.001) relative to A1AT devoid of FA (A1AT-0). These latter effects of A1AT-FA were blocked by inhibitors of peroxisome proliferator-activated receptor (PPAR) ß/δ (ST247) and PPARγ (GW9662). When compared with controls, cell pretreatment with ST247 diminished the effect of A1AT-LA on Angptl4 mRNA (11.6- versus 4.1-fold, p < 0.001) and FABP4 mRNA (5.4- versus 2.8-fold, p < 0.001). Similarly, preincubation of cells with GW9662 inhibited inducing effect of A1AT-LA on Angptl4 mRNA (by 2-fold, p < 0.001) and FABP4 mRNA (by 3-fold, p < 0.001). Thus, A1AT binds to FA, and it is this form of A1AT that induces Angptl4 and FABP4 expression via a PPAR-dependent pathway. These findings provide a mechanism for the unexplored area of A1AT biology independent of its antiprotease properties.
Subject(s)
Angiopoietins/immunology , Gene Expression Regulation/immunology , Linoleic Acid/immunology , Monocytes/immunology , Oleic Acid/immunology , alpha 1-Antitrypsin/immunology , Angiopoietin-Like Protein 4 , Angiopoietins/blood , Fatty Acid-Binding Proteins/blood , Fatty Acid-Binding Proteins/immunology , Female , Humans , Linoleic Acid/blood , Male , Monocytes/metabolism , Oleic Acid/blood , PPAR gamma/immunology , PPAR gamma/metabolism , alpha 1-Antitrypsin/biosynthesisABSTRACT
Linoleic acid (18:2omega6) and alpha-linolenic acid (18:3omega3) represent the parent fats of the two main classes of polyunsaturated fatty acids: the omega-6 (n-6) and the omega-3 (n-3) fatty acids, respectively. Linoleic acid and alpha-linolenic acid both give rise to other long-chain fatty acid derivatives, including gamma-linolenic acid and arachidonic acid (omega-6 fatty acids) and docosahexaenoic acid and eicosapentaenoic acid (omega-3 fatty acids). These fatty acids are showing promise as safe adjunctive treatments for many skin disorders, including atopic dermatitis, psoriasis, acne vulgaris, systemic lupus erythematosus, nonmelanoma skin cancer, and melanoma. Their roles are diverse and include maintenance of the stratum corneum permeability barrier, maturation and differentiation of the stratum corneum, formation and secretion of lamellar bodies, inhibition of proinflammatory eicosanoids, elevation of the sunburn threshold, inhibition of proinflammatory cytokines (tumor necrosis factor-alpha, interferon-gamma, and interleukin-12), inhibition of lipoxygenase, promotion of wound healing, and promotion of apoptosis in malignant cells, including melanoma. They fulfill these functions independently and through the modulation of peroxisome proliferator-activated receptors and Toll-like receptors.
Subject(s)
Epidermis/metabolism , Linoleic Acid/physiology , alpha-Linolenic Acid/physiology , Caspases/metabolism , Dermatitis, Atopic/immunology , Humans , Linoleic Acid/immunology , Linoleic Acid/pharmacokinetics , Lymphocyte Activation , Permeability , Peroxisome Proliferator-Activated Receptors/metabolism , Signal Transduction/immunology , Skin Diseases/immunology , T-Lymphocytes/metabolism , Toll-Like Receptors/metabolism , alpha-Linolenic Acid/immunology , alpha-Linolenic Acid/pharmacokineticsABSTRACT
Autoxidation of linoleic acid (LA) enhanced by Fe(II)/ascorbate generates unsaturated hydroperoxides which undergo further oxidative evolution resulting in a mixture of electrophiles, including epoxyketooctadecenoic acid and dienones with intact C-18 chains as well as oxidative cleavage products such as 4-hydroxy-2(E)-nonenal (HNE), 4-oxo-2(E)-nonenal (ONE), 2(E)-octenal, 9-hydroxy-12-oxo-10(E)-dodecenoic acid, 9,12-dioxo-10(E)-dodecenoic acid, and 11-oxoundec-9(E)-enoic acid. Mass spectrometric (MALDI-TOF-MS and LC-ESI-MS/MS) studies have been performed following incubation of the model protein beta-lactoglobulin with LA, Fe(II), and ascorbate, which identified adducts of these electrophiles with three different protein nucleophiles. Deuterium labeled linoleic acid 17,17,18,18,18-d(5)-(9Z,12Z)-octadeca-9,12-dienoic acid (d(5)-LA) was synthesized to facilitate the detection and characterization of the protein modifications by mass spectrometry. Reduction by NaBH(4) served to trap reversible adducts and to quantify the number of reducible functional groups in each adduct. This study, which mimics the distribution of reactive lipid peroxidation products generated by a continuous low level flux of reactive oxygen species present in vivo under conditions of oxidative stress, confirms that many irreversibly formed adducts previously identified following exposure of model proteins to pure electrophilic modifiers such as HNE and ONE are also generated during in situ oxidation of LA. These adducts include HNE-His Michael adducts (MA), ONE-Lys 4-ketoamide, ONE-Lys pyrrolinone, and a Cys/His-ONE-Lys pyrrole cross-link. However, reversibly formed adducts, such as the HNE-Lys Schiff base, are not present at detectable levels. The isotopic labeling allowed less commonly identified mirror-image adducts derived from the carboxy terminus of LA to be identified. A novel 2-octenoic acid-His MA was discovered.
Subject(s)
Aldehydes/metabolism , Fatty Acids, Monounsaturated/immunology , Fatty Acids, Monounsaturated/metabolism , Linoleic Acid/metabolism , Computational Biology , Kinetics , Lactoglobulins , Linoleic Acid/immunology , Lipid Peroxidation , Mass Spectrometry , Oxidation-Reduction , Oxidative Stress , Schiff BasesABSTRACT
BACKGROUND: It has been argued that a reduction in the Western diet of anti-inflammatory unsaturated lipids, such as n-3 polyunsaturated fatty acids, has contributed to the increase in the frequency and severity of allergic diseases. OBJECTIVE: We investigated whether feeding milk fat enriched in conjugated linoleic acid and vaccenic acids (VAs) ('enriched' milk fat), produced by supplementing the diet of pasture-fed cows with fish and sunflower oil, will prevent development of allergic airway responses. METHODS: C57BL/6 mice were fed a control diet containing soybean oil and diets supplemented with milk lipids. They were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 14 and 28, and challenged intranasally with OVA on day 42. Bronchoalveolar lavage fluid, lung tissues and serum samples were collected 6 days after the intranasal challenge. RESULTS: Feeding of enriched milk fat led to marked suppression of airway inflammation as evidenced by reductions in eosinophilia and lymphocytosis in the airways, compared with feeding of normal milk fat and control diet. Enriched milk fat significantly reduced circulating allergen-specific IgE and IgG1 levels, together with reductions in bronchoalveolar lavage fluid of IL-5 and CCL11. Treatment significantly inhibited changes in the airway including airway epithelial cell hypertrophy, goblet cell metaplasia and mucus hypersecretion. The two major components of enriched milk fat, cis-9, trans-11 conjugated linoleic acid and VA, inhibited airway inflammation when fed together to mice, whereas alone they were not effective. CONCLUSION: Milk fat enriched in conjugated linoleic and VAs suppresses inflammation and changes to the airways in an animal model of allergic airway disease.
Subject(s)
Fats/immunology , Hypersensitivity/immunology , Linoleic Acid/immunology , Lung Diseases, Obstructive/immunology , Lung Diseases, Obstructive/pathology , Milk/immunology , Oleic Acids/immunology , Allergens/immunology , Animals , Cell Survival , Chemokine CCL11/biosynthesis , Eosinophils/cytology , Eosinophils/immunology , Female , Hypersensitivity/metabolism , Hypersensitivity/pathology , Immunoglobulins/biosynthesis , Immunoglobulins/immunology , Interleukin-5/biosynthesis , Lung Diseases, Obstructive/metabolism , Male , Mice , Mice, Inbred C57BLABSTRACT
The present study aimed at analysis of the effects of polyunsaturated fatty acid (PUFA), linoleic acid (LA, C18:2n - 6) and linolenic acid (LNA, C18:3n - 3) on bovine peripheral blood mononuclear cells (PBMC) in vitro. Both mitogen (ConA)-induced proliferative lymphocyte responsiveness during 4 days of culture and eicosanoid (prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4))) production during 36 h were determined in relation to the absence or presence of various concentrations of LA and LNA (0, 1, 5, 25, 125 and 250 microM). Mitogen-driven proliferative responses of lymphocytes tended to be uninfluenced in the presence of lower concentrations of LA, whereas significant inhibition was observed at the higher concentrations of LA (125 and 250 microM). However, increasing amounts of LNA did not affect the proliferation. ConA stimulation induced a clear PGE(2) response, which significantly decreased in the presence of 250 microM of LA. In addition, increasing amounts of LNA, but not LA, led to a significant decrease in LTB(4) levels. However, The production of LTB(4) did not alter due to mitogenic stimulation. In conclusion, the present study shows that bovine mononuclear cells may functionally be influenced by the presence of PUFA in their environment. Further studies need to be conducted to clarify in vivo consequences of these findings in a situation of PUFA enriched rations in ruminants.
Subject(s)
Leukocytes, Mononuclear/drug effects , Linoleic Acid/pharmacology , Lymphocyte Activation/drug effects , alpha-Linolenic Acid/pharmacology , Animals , Cattle , Concanavalin A/immunology , Dinoprostone/analysis , Dinoprostone/immunology , Female , Immunoenzyme Techniques/veterinary , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunology , Leukotriene B4/analysis , Leukotriene B4/immunology , Linoleic Acid/immunology , Lymphocyte Activation/immunology , Scintillation Counting/veterinary , Thymidine/metabolism , alpha-Linolenic Acid/immunologyABSTRACT
Our laboratory has reported that n-3 PUFA can reduce host resistance to Listeria infection, in part, by impairing in vivo IL-12 biosynthesis. Recently, PUFA were shown to be ligands for PPAR, a novel family of nuclear receptors with three isoforms: PPARalpha, PPARdelta/beta and PPARgamma. PPARgamma is expressed in immune cells, such as T cells and macrophages. Two PPARgamma agonists, 15-deoxy-delta(12,14)-prostaglandin (PG) J2 and rosiglitazone, have been shown to have immunomodulatory activity in vitro, including inhibiting IL-12 biosynthesis. We hypothesized that n-3 PUFA inhibit IL-12 production through activating PPARgamma. We used thioglycolate-elicited mouse peritoneal macrophages to study the effect of various fatty acids and their oxidized metabolites on in vitro IL-12 production. Our present results demonstrate that both n-3 and n-6 PUFA can reduce in vitro IL-12 biosynthesis, though less potently than 15-deoxy-PGJ2 and rosiglitazone. GW9662, a PPARgamma antagonist, reversed the inhibitory effect of rosiglitazone, but not that of PUFA. Our present findings suggest that fatty acid-mediated inhibition of IL-12 production is independent of PPARgamma.
Subject(s)
Fatty Acids, Unsaturated/immunology , Interleukin-12/biosynthesis , Macrophages, Peritoneal/immunology , Receptors, Cytoplasmic and Nuclear/immunology , Transcription Factors/immunology , Anilides/immunology , Anilides/metabolism , Animals , Arachidonic Acid/immunology , Cells, Cultured , Docosahexaenoic Acids/immunology , Female , Interleukin-12/immunology , Ligands , Linoleic Acid/immunology , Mice , Mice, Inbred BALB C , Oxidation-Reduction , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Rosiglitazone , Thiazolidinediones/immunology , Transcription Factors/antagonists & inhibitors , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
Increasing evidence indicates the involvement of immune reactions in the pathogenesis of alcoholic liver disease. We have investigated whether ethanol-induced oxidative stress might contribute to immune response in alcoholics. Antibodies against human serum albumin modified by reaction with malondialdehyde (MDA), 4-hydroxynonenal (HNE), 2-hexenal, acrolein, methylglyoxal, and oxidized arachidonic and linoleic acids were measured by ELISA in 78 patients with alcoholic cirrhosis and/or hepatitis, 50 patients with nonalcoholic cirrhosis, 23 heavy drinkers with fatty liver, and 80 controls. Titers of IgG-recognizing epitopes derived from MDA, HNE, and oxidized fatty acids were significantly higher in alcoholic as compared to nonalcoholic cirrhotics or healthy controls. No differences were instead observed in the titers of IgG-recognizing acrolein-, 2-hexenal-, and methylglyoxal-modified albumin. Alcoholics showing high IgG titers to one adduct tended to have high titers to all the others. However, competition experiments showed that the antigens recognized were structurally unrelated. Anti-MDA and anti-HNE antibodies were significantly higher in cirrhotics with more severe disease as well as in heavy drinkers with cirrhosis or extensive fibrosis than in those with fatty liver only. We conclude that antigens derived from lipid peroxidation contribute to the development of immune responses associated with alcoholic liver disease.
Subject(s)
Immunoglobulin G/blood , Lipid Peroxidation/immunology , Liver Diseases, Alcoholic/immunology , Acrolein/chemistry , Acrolein/immunology , Adult , Aged , Aldehydes/chemistry , Aldehydes/immunology , Arachidonic Acid/chemistry , Arachidonic Acid/immunology , Arachidonic Acid/metabolism , Ethanol/metabolism , Female , Humans , Immunoglobulin G/immunology , Linoleic Acid/chemistry , Linoleic Acid/immunology , Linoleic Acid/metabolism , Liver Diseases, Alcoholic/blood , Male , Malondialdehyde/chemistry , Malondialdehyde/immunology , Middle Aged , Oxidation-Reduction , Oxidative Stress/physiology , Serum Albumin/chemistry , Serum Albumin/immunologyABSTRACT
The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n-3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n-3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory and immunomodulatory.
Subject(s)
Eicosanoids/metabolism , Fatty Acids, Unsaturated/physiology , Immune System/physiology , Inflammation/immunology , Animals , Arachidonic Acid/immunology , Arachidonic Acid/metabolism , Arachidonic Acid/pharmacology , Fatty Acids, Unsaturated/pharmacology , Fish Oils/pharmacology , Humans , Immune System/drug effects , Immune System Diseases/metabolism , Immune System Diseases/physiopathology , Immunity , Infant , Infant Food , Inflammation/physiopathology , Linoleic Acid/immunology , Linoleic Acid/metabolism , Th1 Cells/drug effects , Th1 Cells/immunology , Th2 Cells/drug effects , Th2 Cells/immunologyABSTRACT
Review of the evidence available in published literature supports a radical change in viewpoint with respect to disease in countries where maize is the predominant dietary component. In these countries, the pattern of disease is largely determined by a change in immune profile caused by metabolites of dietary linoleic acid. High intake of linoleic acid in a diet deficient in other polyunsaturated fatty acids and in riboflavin results in high tissue production of prostaglandin E2, which in turn causes inhibition of the proliferation and cytokine production of Th1 cells, mediators of cellular immunity. Tuberculosis, measles, hepatoma, secondary infection in HIV and kwashiorkor are all favoured by this reduction in cellular immunity. Diet-associated inhibition of the Th1 subset is a major contributor to the high prevalence of these diseases found in areas of sub-Saharan Africa where maize is the staple.