linoleic-acid and hydroxyoctadecadienoic-acid

Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo-​octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner. Chemical Compounds: Linoleic acid (PubChem CID: 5280450), 9- hydroxyoctadecadienoic acid (PubChem CID: 5312830), 13- hydroxyoctadecadienoic acid (PubChem CID: 6443013), 9-oxo-​octadecadienoic acid (PubChem CID: 3083831), 13-oxo-​octadecadienoic acid (PubChem CID: 4163990), 9,10-epoxy-12-octadecenoate (PubChem CID: 5283018), 12,13-epoxy-9-keto-10- trans -octadecenoic acid (PubChem CID: 53394018), Pioglitazone (PubChem CID: 4829).

Topics: Animals; Fatty Acids, Unsaturated; Humans; Inflammation; Linoleic Acid; Metabolic Syndrome; Neoplasms; Oxidation-Reduction

We developed a novel method to measure hydroxyoctadecadienoic acid (HODE) levels in biological fluids and tissue samples. This method can be used to measure the oxidation products of linoleic acid. Reduction and saponification enabled us to measure hydroperoxides and hydroxides of both free and esterified forms of linoleic acid as total HODE, which includes the enzymatic and non-enzymatic products 9- and 13-(Z, E)-HODEs; the non-enzymatic free radical-mediated products 9- and 13-(E, E)-HODEs; and the specific non-enzymatic singlet oxygen-mediated products 10- and 12-(Z, E)-HODEs. We have recently reported HODE levels in plasma and erythrocytes from healthy volunteers and patients with several diseases and determined that its levels are much higher in patients with lifestyle-related diseases than in healthy volunteers. Furthermore, 10- and 12-(Z, E)-HODE plasma levels can serve as promising biomarkers for the early detection of diabetes. Thus, HODE is a useful biomarker for the assessment of oxidative status, and its efficiency as a biomarker can be improved by using it in combination with other typical biomarkers. This review article focuses on lipid peroxidation biomarkers, including HODE, and discusses their potential in practical and clinical applications in disease prediction.

Topics: Biomarkers; Diabetes Mellitus; Early Diagnosis; Fatty Acids, Unsaturated; Humans; Life Style; Linoleic Acid; Lipid Peroxidation; Lipid Peroxides; Oxidative Stress

Longer-chain polyunsaturated fatty acids (LCPUFAs) ≥20 carbons long are required for leukocyte function. These can be obtained from the diet, but there is some evidence that leukocytes can convert essential fatty acids (EFAs) into LCPUFAs. We used stable isotope tracers to investigate LCPUFA biosynthesis and the effect of different EFA substrate ratios in human T lymphocytes. CD3

Topics: Adolescent; Adult; alpha-Linolenic Acid; Cells, Cultured; Fatty Acid Desaturases; Fatty Acid Elongases; Fatty Acids, Essential; Fatty Acids, Unsaturated; Female; Gas Chromatography-Mass Spectrometry; Humans; Linoleic Acid; Lipid Metabolism; Lymphocyte Activation; Male; T-Lymphocytes; Young Adult

Lung cancer is the leading cause of cancer-related mortality. Surgical removal of the tumor at an early stage can be curative. However, lung cancer diagnosis at an early stage remains challenging. There is evidence that free fatty acids play a role in cancer development.. Serum samples from 55 patients with lung cancer were propensity matched with samples from 165 similar pulmonary patients without known cancer. Patients were propensity matched on age, sex, smoking history, family history of lung cancer, and chronic diseases that might affect free fatty acid levels.. Free fatty acids arachidonic acid (AA) and linoleic acid (LA) and their metabolites hydroxyeicosatetraenoic acids (HETEs)(5-HETE, 11-HETE, 12-HETE, and 15-HETE) were an estimated 1.8- to 3.3-fold greater in 37 patients with adenocarcinoma vs 111 patients without cancer (all P < .001). Areas under the receiver operating characteristic curve were significantly > 0.50, discriminating patients with lung cancer and control subjects for six of eight biomarkers and two of seven phospholipids tested, and ranged between 0.69 and 0.82 (all P < .001) for patients with lung cancer vs control subjects. AA, LA, and 15-HETE had observed sensitivity and specificity > 0.70 at the best cutpoint. Concentrations of free fatty acids and their metabolites were similar in 18 patients with squamous cell carcinoma and 54 control subjects without cancer.. Serum fatty acids and their metabolites demonstrate good sensitivity and specificity for the identification of adenocarcinoma of the lung.

Topics: Adenocarcinoma; Adult; Aged; Area Under Curve; Biomarkers; Case-Control Studies; Fatty Acids, Nonesterified; Fatty Acids, Unsaturated; Female; Humans; Hydroxyeicosatetraenoic Acids; Linoleic Acid; Lung Neoplasms; Male; Middle Aged; Phospholipids; Sensitivity and Specificity

Macrophage apoptosis, a key process in atherogenesis, is regulated by oxidation products, including hydroxyoctadecadienoic acids (HODEs). These stable oxidation products of linoleic acid (LA) are abundant in atherosclerotic plaque and activate PPARγ and GPR132. We investigated the mechanisms through which HODEs regulate apoptosis. The effect of HODEs on THP-1 monocytes and adherent THP-1 cells were compared with other C18 fatty acids, LA and α-linolenic acid (ALA). The number of cells was reduced within 24 hours following treatment with 9-HODE (p < 0.01, 30 μM) and 13 HODE (p < 0.01, 30 μM), and the equivalent cell viability was also decreased (p < 0.001). Both 9-HODE and 13-HODE (but not LA or ALA) markedly increased caspase-3/7 activity (p < 0.001) in both monocytes and adherent THP-1 cells, with 9-HODE the more potent. In addition, 9-HODE and 13-HODE both increased Annexin-V labelling of cells (p < 0.001). There was no effect of LA, ALA, or the PPARγ agonist rosiglitazone (1 μM), but the effect of HODEs was replicated with apoptosis-inducer camptothecin (10 μM). Only 9-HODE increased DNA fragmentation. The pro-apoptotic effect of HODEs was blocked by the caspase inhibitor DEVD-CHO. The PPARγ antagonist T0070907 further increased apoptosis, suggestive of the PPARγ-regulated apoptotic effects induced by 9-HODE. The use of siRNA for GPR132 showed no evidence that the effect of HODEs was mediated through this receptor. 9-HODE and 13-HODE are potent--and specific--regulators of apoptosis in THP-1 cells. Their action is PPARγ-dependent and independent of GPR132. Further studies to identify the signalling pathways through which HODEs increase apoptosis in macrophages may reveal novel therapeutic targets for atherosclerosis.

Topics: alpha-Linolenic Acid; Apoptosis; Caspase 3; Caspase 7; Cell Cycle Proteins; Cell Line; Cell Survival; DNA Fragmentation; Fatty Acid-Binding Proteins; Fatty Acids, Unsaturated; Gene Expression Regulation; Humans; Linoleic Acid; Linoleic Acids; Linoleic Acids, Conjugated; Monocytes; PPAR gamma; Receptors, G-Protein-Coupled; RNA, Small Interfering; Rosiglitazone; Signal Transduction; Thiazolidinediones

Jasmonic acid (JA) is synthesized from linolenic acid (18:3n-3) by sequential action of 13-lipoxygenase, allene oxide synthase (AOS), and allene oxide cyclase. The fungus Lasiodiplodia theobromae can produce large amounts of JA and was recently reported to form the JA precursor 12-oxophytodienoic acid. The objective of our study was to characterize the fatty acid dioxygenase activities of this fungus. Two strains of L. theobromae with low JA secretion (~0.2 mg/L medium) oxygenated 18:3n-3 to 5,8-dihydroxy-9Z,12Z,15Z-octadecatrienoic acid as well as 9R-hydroperoxy-10E,12Z,15Z-octadecatrienoic acid, which was metabolized by an AOS activity into 9-hydroxy-10-oxo-12Z,15Z-octadecadienoic acid. Analogous conversions were observed with linoleic acid (18:2n-6). Studies using [11S-(2)H]18:2n-6 revealed that the putative 9R-dioxygenase catalyzed stereospecific removal of the 11R hydrogen followed by suprafacial attack of dioxygen at C-9. Mycelia from these strains of L. theobromae contained 18:2n-6 as the major polyunsaturated acid but lacked 18:3n-3. A third strain with a high secretion of JA (~200 mg/L) contained 18:3n-3 as a major fatty acid and produced 5,8-dihydroxy-9Z,12Z,15Z-octadecatrienoic acid from added 18:3n-3. This strain also lacked the JA biosynthetic enzymes present in higher plants.

Topics: alpha-Linolenic Acid; Ascomycota; Chromatography, Reverse-Phase; Cyclopentanes; Dioxygenases; Fatty Acids, Unsaturated; Intramolecular Oxidoreductases; Linoleic Acid; Lipid Metabolism; Lipoxygenase; Mycelium; Oxylipins; Plant Growth Regulators; Plants; Tandem Mass Spectrometry

Acute inflammation is a common feature of many life-threatening pathologies, including septic shock. One hallmark of acute inflammation is the peroxidation of polyunsaturated fatty acids forming bioactive products that regulate inflammation. Myeloperoxidase (MPO) is an abundant phagocyte-derived hemoprotein released during phagocyte activation. Here, we investigated the role of MPO in modulating biologically active arachidonic acid (AA) and linoleic acid (LA) metabolites during acute inflammation. Wild-type and MPO-knockout (KO) mice were exposed to intraperitoneally injected endotoxin for 24 h, and plasma LA and AA oxidation products were comprehensively analyzed using a liquid chromatography-mass spectrometry method. Compared to wild-type mice, MPO-KO mice had significantly lower plasma levels of LA epoxides and corresponding LA- and AA-derived fatty acid diols. AA and LA hydroxy intermediates (hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids) were also significantly lower in MPO-KO mice. Conversely, MPO-deficient mice had significantly higher plasma levels of cysteinyl-leukotrienes with well-known proinflammatory properties. In vitro experiments revealed significantly lower amounts of AA and LA epoxides, LA- and AA-derived fatty acid diols, and AA and LA hydroxy intermediates in stimulated polymorphonuclear neutrophils isolated from MPO-KO mice. Our results demonstrate that MPO modulates the balance of pro- and anti-inflammatory lipid mediators during acute inflammation and, in this way, may control acute inflammatory diseases.

Topics: Animals; Arachidonic Acid; Chromatography, Liquid; Disease Models, Animal; Epoxy Compounds; Fatty Acids, Unsaturated; Hydroxyeicosatetraenoic Acids; Inflammation; Linoleic Acid; Lipopolysaccharides; Male; Mass Spectrometry; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Peroxidase; Shock, Septic

The transient receptor potential vanilloid 1 (TRPV1) channel is the principal detector of noxious heat in the peripheral nervous system. TRPV1 is expressed in many nociceptors and is involved in heat-induced hyperalgesia and thermoregulation. The precise mechanism or mechanisms mediating the thermal sensitivity of TRPV1 are unknown. Here, we have shown that the oxidized linoleic acid metabolites 9- and 13-hydroxyoctadecadienoic acid (9- and 13-HODE) are formed in mouse and rat skin biopsies by exposure to noxious heat. 9- and 13-HODE and their metabolites, 9- and 13-oxoODE, activated TRPV1 and therefore constitute a family of endogenous TRPV1 agonists. Moreover, blocking these substances substantially decreased the heat sensitivity of TRPV1 in rats and mice and reduced nociception. Collectively, our results indicate that HODEs contribute to the heat sensitivity of TRPV1 in rodents. Because oxidized linoleic acid metabolites are released during cell injury, these findings suggest a mechanism for integrating the hyperalgesic and proinflammatory roles of TRPV1 and linoleic acid metabolites and may provide the foundation for investigating new classes of analgesic drugs.

Topics: Animals; Fatty Acids, Unsaturated; Hot Temperature; Ligands; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Models, Biological; Oxygen; Pain; Rats; Rats, Sprague-Dawley; TRPV Cation Channels

Adipocere formation is well known as a later post-mortem change. We experienced a female victim who had been sealed up in a clothes box for approximately 4 years. We collected several subcutaneous fats as well as visceral fats from the victim to investigate adipocere formation. Fresh subcutaneous fats of one female and five male victims who suddenly died were used as the control. These samples were homogenized and the lipids were extracted with chloroform and methanol followed by injection into gas chromatography-mass spectrometry and gas chromatography. We detected a hydroxy fatty acid in the fat of the case, but not in the controls. Using standard synthetic hydroxy fatty acid, the lipid extract component was identified as 10-hydroxyoctadecanoic acid (10-OH 18:0) and this concentration was quantified. Consequently we confirmed that adipocere was formed much slowly in dry concealment. In addition, the fatty acid composition was compared with the control. Most of the linoleic acid (18:2) disappeared and a peak developed instead. Using standard synthetic fatty acid, this peak was identified as cis-12-octadecenoic acid (cis-12-18:1). This suggests that linoleic acid is hydrogenated to cis-12-octadecenoic acid in the process of adipocere formation.

Topics: Aged; Case-Control Studies; Chromatography, Gas; Environment, Controlled; Fatty Acids, Unsaturated; Female; Forensic Pathology; Humans; Hydrogenation; Linoleic Acid; Male; Postmortem Changes; Stearic Acids