linoleic-acid and Necrosis

Triacylglycerols (TGs) are being considered as an independent risk factor in atherosclerosis and metabolic syndrome, acting by dysregulation of the TG/high-density lipoprotein axis. Accumulation of lipids in subendothelial space attracts macrophages, leading to atherosclerotic plaque formation and increased plaque instability due to formation of foam cells and macrophage death. The aim of this study was to evaluate lipotoxic effects in macrophages caused by TG uptake.. J774.2 macrophages were exposed to soybean or olive oil-based lipid emulsions as a source of TGs (1 mg/mL) in a presence or absence of lipase inhibitor paraoxon (20 microM) or to bovine serum albumin-complexed palmitic (150 microM), linoleic (600 microM), and oleic (600 microM) fatty acids.. The results demonstrated accumulation of TGs, G1/S arrest, and cell death with necrotic morphologic features after exposure to TG emulsions. These effects were prevented by treatment with an antioxidant N-acetyl-cysteine (0.5 mM). Paraoxon inhibited intracellular TG degradation but did not prevent lipotoxicity and cell death. Olive oil TG triggered macrophage death in a manner similar to soybean oil. Treatment of the macrophages with free fatty acid, mainly with palmitic acid, showed a reactive oxygen species-independent cell death pathway, which was different from that of TG and was not prevented by N-acetyl-cysteine.. This study shows a direct lipotoxic pathway for TG molecules in macrophages, which is not associated with degradation of TG molecule to free fatty acids. This study for the first time can explain at a cellular level how TGs as an independent risk factor aggravate atherosclerotic outcomes.

Topics: Animals; Cell Cycle; Cell Death; Cell Line; DNA; Linoleic Acid; Macrophages; Mice; Necrosis; Oleic Acid; Olive Oil; Oxidative Stress; Palmitic Acid; Paraoxon; Plant Oils; Reactive Oxygen Species; Serum Albumin, Bovine; Soybean Oil; Time Factors; Triglycerides

The authors investigated whether fatty acid emulsion affects the blood-brain barrier (BBB), whether disrupted BBB is reversible, and whether the fatty acid emulsion technique may be a model for BBB research.. The fat emulsion was made with 0.05 mL of oleic acid or linoleic acid and 20 mL of normal saline. The internal carotid artery in 14 cats was infused with oleic acid emulsion (group 1) and with linoleic acid emulsion in 12 cats (group 2). Gd-enhanced T1-weighted (Gd-T1WI), diffusion-weighted (DWI), and additional apparent diffusion coefficient (ADC) map magnetic resonance imaging (MRI) was obtained at 1 hour, 1 and 4 days, and 1 week after infusion. MRI findings were evaluated qualitatively. Quantitatively, the signal intensity ratio (SIR) of the lesion to the contralateral hemisphere was measured on Gd-T1WIs. The SIRs were statistically analyzed using the student t test. The brain tissue was removed immediately for light and electron microscopy examination if the lesion showed no contrast enhancement and was isointense on DWIs and the ADC maps.. The lesions appeared at 1 hour in both groups as contrast enhancement on Gd-T1WIs, as isointensity or mild hyperintensity on DWIs, and as isointensity on the ADC maps. On day 1, these MRI findings were decreased in group 1 and were not seen in group 2. At 1 hour, the SIRs of group 1 were significantly higher than those of group 2 (P = 0.016). On day 1, the SIRs of both groups approximated 1.0. Light microscopy findings revealed minor necrosis and demyelination in one cat from group 1 and in 3 cats from group 2. Electron microscopy examinations showed minimal findings in the cortical lesions in groups 1 and 2.. Infusion of unsaturated fatty acid emulsion into the carotid artery of cats revealed vasogenic edema of the brain and reversible changes as depicted on MRI. This unsaturated fat emulsion technique may be used as a model for research on BBB disruption.

Topics: Animals; Blood-Brain Barrier; Brain; Brain Edema; Carotid Artery, Internal; Cats; Demyelinating Diseases; Diffusion Magnetic Resonance Imaging; Disease Models, Animal; Emulsions; Gadolinium DTPA; Image Enhancement; Injections, Intra-Arterial; Linoleic Acid; Necrosis; Oleic Acid; Time Factors

Lipid emulsions for parenteral nutrition commercially available are mainly composed of long-chain triacylglycerol containing a high proportion of alpha-6 polyunsaturated fatty acids or alpha-9 monounsaturated fatty acids. The immunological impact of such therapy is particularly important because parenteral and enteral diets are often administered to critical ill patients. The comparative toxicity of oleic acid and linoleic acid on Jurkat cells, a human T lymphocyte cell line, and the type of cell death induced by these fatty acids were determined.. Cell death was investigated by cytometry: decrease in cell volume, increase of granularity, DNA fragmentation, phosphatidylserine externalization, mitochondrial depolarization, lipid accumulation; by fluorescence microscopy: chromatin condensation and acridine orange/ethidium bromide assay; and by RT-PCR: mRNA expression of apoptotic genes.. Evidence is presented herein that oleic acid is much less toxic to Jurkat cells than linoleic acid. Both fatty acids promote apoptosis and necrosis of these cells. The mechanism of cell death induced by these fatty acids seem to involve with mitochondrial depolarization, lipid accumulation and the levels of C-MYC and P53 mRNA expression.. Therefore, oleic acid may offer an immunological less harmful alternative to linoleic acid for parenteral and enteral diets preparation.

Topics: Apoptosis; Cell Survival; DNA Fragmentation; Dose-Response Relationship, Drug; Flow Cytometry; Humans; Jurkat Cells; Linoleic Acid; Necrosis; Oleic Acid; Parenteral Nutrition; Reverse Transcriptase Polymerase Chain Reaction; Time Factors

Both n-6 and n-3 polyunsaturated fatty acids are dietary fats important for cell function, being involved in several physiologic and pathologic processes, such as tumorigenesis. Linoleic acid and conjugated linoleic acid, its geometrical and positional stereoisomer, were tested on several human tumor cell lines originating from different tissues and with different degrees of malignancy. This was to provide the widest possible view of the impact of dietary lipids on tumor development. While linoleic acid exerted different effects, ranging from inhibitory to neutral, even promoting growth, conjugated linoleic acid inhibited growth in all lines tested and was particularly effective against the more malignant cells, with the exception of mammary tumor cells, in which behavior was the opposite, the more malignant cell line being less affected. The inhibitory effect of conjugated linoleic acid on growth may be accompanied by different contributions from apoptosis and necrosis. The effects of conjugated linoleic acid on growth or death involved positive or negative variations in PPARs. The important observation is that a big increase of PPARalpha protein occurred in cells undergoing strong induction of apoptosis, whereas PPARbeta/delta protein decreased. Although PPARalpha and PPARbeta/delta seem to be correlated to execution of the apoptotic program, the modulation of PPARgamma appears to depend on the type of tumor cell, increasing as protein content, when inhibition of cell proliferation occurred. In conclusion, CLA may be regarded as a component of the diet that exerts antineoplastic activity and its effect may be antiproliferative or pro-apoptotic.

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Carcinoma; Carcinoma, Hepatocellular; Cell Line, Tumor; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Linoleic Acid; Linoleic Acids, Conjugated; Liver Neoplasms; Necrosis; Neoplasms; Peroxisome Proliferator-Activated Receptors; PPAR alpha; PPAR delta; PPAR gamma; PPAR-beta; Urinary Bladder Neoplasms

Despite many studies elucidating the mechanisms of necrotic cell death, the role of fatty acids released during necrosis remains to be determined. The goals of this study were to determine whether linoleic acid could protect rabbit renal proximal tubules (RPT) from necrotic cell death associated with mitochondrial dysfunction and oxidative injury and to determine the mechanisms involved. Exposure to antimycin A (10 microM) for 1 h or hypoxia (perfusion with 95% N(2)/5% CO(2)) for 1 or 2 h induced approximately 70% cellular lysis, as measured by lactate dehyrogenase release, versus 10% in controls. Preincubation with linoleic acid (100 microM) fully protected RPT from cellular lysis. RPT were also protected from lysis if linoleic acid was added 15 min after the addition of antimycin A. Measurements of free intracellular Ca(2+) concentrations showed that linoleic acid did not prevent the rise in intracellular Ca(2+) associated with a 30-min exposure to antimycin A. However, the influx of extracellular (36)Cl(-) following a 30-min exposure to antimycin A was ameliorated in the presence of linoleic acid. Linoleic acid did not prevent cellular lysis after exposure to hypoxia/reoxygenation (1 h/1 h) or t-butyl hydroperoxide (500 microM, 3 h). These data suggest that linoleic acid protects RPT during the late phase of cell death associated with inhibition of the electron transport chain but not oxidative injury. Several other fatty acids also protected RPT from lysis, and structure-activity relationship studies suggest that a free carboxyl terminus and at least one double bond are required for this action.

Topics: Animals; Antimycin A; Calcium; Cell Death; Chlorides; Electron Transport; Fatty Acids; Female; Kidney Tubules, Proximal; L-Lactate Dehydrogenase; Linoleic Acid; Mitochondria; Necrosis; Rabbits

To evaluate the possible role of essential fatty acids, specifically gamma-linolenic and eicosapentaenoic acid, in the amelioration of early and late radiation damage to the skin.. Skin sites on the flank of 22-25 kg female large white pigs were irradiated with either single or fractionated doses (20 F/28 days) of beta-rays from 22.5 mm diameter 90Sr/90Y plaques at a dose rate of approximately 3 Gy/min. Essential fatty acids were administered orally in the form of two 'active' oils, So-1100 and So-5407, which contained gamma-linolenic acid and a mixture of that oil with eicosapentaenoic acid, respectively. Oils (1.5-6.0 ml) were given daily for 4 weeks prior, both 4 weeks prior and 10-16 weeks after, or in the case of one single dose study, just for 10 weeks after irradiation. Control animals received a 'placebo' oil, So-1129, containing no gamma linolenic acid or eicosapentaenoic acid over similar time scales before and after irradiation. Acute and late skin reactions were assessed visually and the dose-related incidence of a specific reaction used to compare the effects of different treatment schedules.. A reduction in the severity of both the early and late radiation reactions in the skin was only observed when 'active' oils were given over the time course of the expression of radiation damage. Prior treatment with oils did not modify the radiation reaction. A 3.0 ml daily dose of either So-1100 or So-5407 given prior to, but also after irradiation with single and fractionated doses of beta-rays produced the most significant modification to the radiation reactions, effects consistent with dose modification factors between 1.06-1.24 for the acute reactions of bright red erythema and/or moist desquamation, and of 1.14-1.35 for the late reactions of dusky/mauve erythema and dermal necrosis. There was the strong suggestion of an effect produced by the 'placebo' oil, So-1129, after higher daily doses of oil.. Essential fatty acids can modulate normal tissue reactions when given over the time when radiation damage is normally expressed. Dose modification factors suggest that a > or = 10% higher dose is required to produce the same level of normal tissue injury. Clinical application of selected essential fatty acids at appropriate doses may lead to a significant increase in the therapeutic gain in patients treated for cancer by radiotherapy.

Topics: Animals; Beta Particles; Eicosapentaenoic Acid; Fatty Acids, Essential; Female; gamma-Linolenic Acid; Linoleic Acid; Linoleic Acids; Necrosis; Radiation Injuries, Experimental; Skin; Strontium; Swine; Yttrium Radioisotopes

For 16 wk Atlantic salmon (Salmo salar) post-smolts were fed practical-type diets that contained either fish oil (FO) or sunflower oil (SO) as the lipid component. Both diets contained adequate (n-3) polyunsaturated fatty acids (PUFA). All the phospholipids of heart and liver from SO-fed fish had increased levels of 18:2(n-6), 20:2(n-6) and 20:3(n-6); phosphatidyl choline (PC) and phosphatidyl ethanolamine (PE) also had increased 20:4(n-6). There was a general decrease in 20:5(n-3) in the phospholipids, reflected in an increase in the 20:4(n-6)/20:5(n-3) ratio, especially in PC and PE. The fatty acid compositions of phospholipids from brain and retina were much less affected by dietary linoleate than those of heart and liver. Fish fed SO developed severe heart lesions that caused thinning of the ventricular wall and muscle necrosis. The fish fed SO also were susceptible to a transportation-induced shock syndrome that caused 30% mortality. These results establish that a diet with a low (n-3)/(n-6) ratio can cause changes in fatty acid metabolism that are deleterious to the health of salmonid fish, especially when subjected to stress.

Topics: Animals; Brain; Dietary Fats, Unsaturated; Fatty Acids; Fish Oils; Heart; Heart Diseases; Linoleic Acid; Linoleic Acids; Liver; Myocardium; Necrosis; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Plant Oils; Retina; Salmon; Stress, Physiological; Sunflower Oil

We studied whether linoleic acid, a precursor for arachidonic acid and prostaglandins, could protect the gastric mucosa against ethanol-induced injury. Fasted male rats received intragastric pretreatment with 1 ml of one of: a) solubilizer; b) solubilized linoleic acid (74 mg); or c) solubilized oleic acid (74 mg) (a nonessential fatty acid). One hour later, 2 ml 100% ethanol was given intragastrically. Three hours after ethanol administration, the gastric mucosa was assessed for gross necrosis and for histologic changes. Three hours after ethanol administration in solubilizer, pretreated-group gross mucosal necrosis involved 35 +/- 3% of total mucosal area, while deep histologic necrosis involved 52 +/- 4% of the mucosal strip length. Pretreatment with linoleic acid (but not oleic acid) significantly reduced gross histologic necrosis, to 2.3 +/- 0.5%, and deep histologic necrosis to 4 +/- 2% (both p less than 0.001 versus solubilizer group). The protective action of linoleic acid was significantly reduced (greater than 10-fold) by pretreatment with indomethacin (prostaglandins synthetase inhibitor), suggesting prostaglandins as mediators of protection. The present study showed that effective protection of the gastric mucosa against ethanol injury can be achieved by intragastric administration of linoleic acid, a dietary essential fatty acid.

Topics: Animals; Ethanol; Gastric Mucosa; Linoleic Acid; Linoleic Acids; Male; Necrosis; Rats; Rats, Inbred Strains

Topics: Electrons; Inflammation; Linoleic Acid; Linoleic Acids; Lipidoses; Lung Diseases; Microscopy; Microscopy, Electron; Necrosis; Oleic Acid; Oleic Acids; Rats; Research