linoleic-acid and Chronic-Disease

The intake of linoleic acid (LA) has increased dramatically in the standard American diet. LA is generally promoted as supporting human health, but there exists controversy regarding whether the amount of LA currently consumed in the standard American diet supports human health. The goal of this narrative review is to explore the mechanisms that underlie the hypothesis that excessive LA intake may harm human health. While LA is considered to be an essential fatty acid and support health when consumed in modest amounts, an excessive intake of LA leads to the formation of oxidized linoleic acid metabolites (OXLAMs), impairments in mitochondrial function through suboptimal cardiolipin composition, and likely contributes to many chronic diseases that became an epidemic in the 20th century, and whose prevalence continues to increase. The standard American diet comprises 14 to 25 times more omega-6 fatty acids than omega-3 fatty acids, with the majority of omega-6 intake coming from LA. As LA consumption increases, the potential for OXLAM formation also increases. OXLAMs have been associated with various illnesses, including cardiovascular disease, cancer, and Alzheimer's disease, among others. Lowering dietary LA intake can help reduce the production and accumulation of OXLAMs implicated in chronic diseases. While there are other problematic components in the standard American diet, the half-life of LA is approximately two years, which means the damage can be far more persistent than other dietary factors, and the impact of reducing excessive LA intake takes time. Therefore, additional research-evaluating approaches to reduce OXLAM formation and cardiolipin derangements following LA consumption are warranted.

Topics: Cardiolipins; Chronic Disease; Diet; Humans; Linoleic Acid

The possibility that western diets poor in omega-3 and rich in omega-6 fatty acids contribute to the increasing burden of chronic diseases including neurological problems is becoming recognized. Modern, westernized diets provide 80 to 90% of polyunsaturated fatty acids as omega-6 linoleic acid (LA) and are depleted in omega-3 fatty acids, giving a distorted balance of LA to α-linoleic acid, and to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). LA intakes exceed Δ-6 desaturase needs for maximal activity. LA accumulates in blood and tissue lipids with increasing intake, and this exacerbates competition between LA and limited omega-3 fatty acids for metabolism and acylation into tissue lipids. Increasing EPA and DHA intake decreases tissue omega-6 fatty acids while also providing EPA and DHA. However, strategies for EPA and DHA supplementation do not address potential underlying problems of omega-6 and omega-3 fatty acid imbalance in the food supply.

Topics: alpha-Linolenic Acid; Chronic Disease; Diet, Western; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Humans; Linoleic Acid; Nutritional Physiological Phenomena; Tissue Distribution

Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a lower omega-6/omega-3 ratio), exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries.

Topics: alpha-Linolenic Acid; Biological Evolution; Blood Platelets; Cardiovascular Diseases; Cell Proliferation; Chronic Disease; Colorectal Neoplasms; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Humans; Linoleic Acid; Models, Biological; Platelet Aggregation; Risk

Modern separation and identification methods enable detailed insight in lipid peroxidation (LPO) processes. The following deductions can be made: (1) Cell injury activates enzymes: lipoxygenases generate lipid hydroperoxides (LOOHs), proteases liberate Fe ions--these two processes are prerequisites to produce radicals. (2) Radicals attack any activated CH2-group of polyunsaturated fatty acids (PUFAs) with about a similar probability. Since linoleic acid (LA) is the most abundant PUFA in mammals, its LPO products dominate. (3) LOOHs are easily reduced in biological surroundings to corresponding hydroxy acids (LOHs). LOHs derived from LA, hydroxyoctadecadienoic acids (HODEs), surmount other markers of LPO. HODEs are of high physiological relevance. (4) In some diseases characterized by inflammation or cell injury HODEs are present in low density lipoproteins (LDL) at 10-100 higher concentration, compared to LDL from healthy individuals.

Topics: Aging; Antioxidants; Chemical Phenomena; Chemistry, Physical; Chronic Disease; Endopeptidases; Free Radicals; Humans; Linoleic Acid; Lipid Peroxidation; Lipid Peroxides; Lipoproteins, LDL; Lipoxygenase; Models, Chemical

The usefulness of micronutrient antioxidant therapy for recurrent (non-gallstone) pancreatitis has recently been endorsed by a 20-week double-blind double-dummy cross-over trial in 20 patients. Treatment was delivered as two types of tablets, providing daily doses of 600 micrograms organic selenium, 9000 i.u. beta-carotene, 0.54 g vitamin C, 270 i.u. vitamin E and 2 g methionine. We report antioxidant profiles in blood samples collected before entry, at the cross-over stage and upon completion of trial. Baseline serum concentrations of selenium, beta-carotene and vitamin E in the patients were significantly lower than in healthy controls, were unaltered by placebo and normalized by active treatment, but reverted to basal values in the subgroup that received placebo subsequently. The baseline serum concentration of a free radical marker--the 9-cis, 11-trans isomer of linoleic acid--was significantly higher in the patients than in controls, fell inexplicably in the placebo phase and fell further upon active treatment. Discriminant analysis eliminated the overlap in free radical marker and selenium concentrations between control sera on the one hand and baseline or post-placebo samples from the patients on the other: antioxidant treatment normalized the relationship between these biochemical parameters. Subnormal baseline serum levels of S-adenosylmethionine drifted downwards upon active treatment whereas a sharp rise was noted when a relapse of pancreatitis occurred during the placebo phase. The results confirm that adequate exposure to antioxidants in the active treatment phase was associated with amelioration of oxidative stress, and that there was no residual effect 10 weeks after switching over to placebo treatment. Furthermore, the paradoxical behaviour of S-adenosylmethionine may imply that the beneficial effect of micronutrient antioxidants in recurrent pancreatitis is linked with preservation of the methionine trans-sulfuration pathway in pancreatic acinar cells.

Topics: Acute Disease; Adolescent; Adult; Aged; Antioxidants; Chronic Disease; Double-Blind Method; Female; Free Radicals; Glutathione Peroxidase; Humans; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Pancreatitis; S-Adenosylmethionine; Selenium

To investigate the changes in fatty acid composition of serum cholesteryl esters in patients with chronic heart failure (CHF).. The levels of serum TG, TC, HDL, and LDL in 36 patients with CHF and 20 healthy controls were measured and fatty acid cholesteryl esters were determined by high performance liquid chromatography.. In the patients with CHF, the level of linoleic acid was significantly higher than that in the control group (P < 0.05), but the level of arachidonic acid was significantly lower than that in the control group (P < 0.05). The levels of TC, TG, HDL, and LDL were not significantly different between the two groups.. Changes in fatty acid composition of serum cholesteryl esters exist in the patients with CHF.

Topics: Adult; Aged; Arachidonic Acid; Cholesterol; Cholesterol Esters; Chronic Disease; Fatty Acids; Female; Heart Failure; Humans; Linoleic Acid; Male; Middle Aged; Triglycerides

In acute liver failure the liver has to regenerate, which may increase the consumption of essential fatty acids. Nutritional support consists mainly of infusion of glucose. It is therefore possible that essential fatty acid deficiency may develop in such patients.. Plasma phospholipid composition was studied in healthy controls (n=11), in patients with acute liver failure, (n=10), in patients with stable cirrhosis (n=7), and in patients with acute on chronic liver disease with hepatic encephalopathy (n=6). The influence of 2 days of fat-free diet followed by infusion of glucose was studied in five healthy controls.. The ratio between the sums of nonessential/ essential fatty acids, (n-7+n-9)/(n-3+n-6), was higher in patients with acute liver failure (0.73+/-0.17) compared to healthy controls (0.35+/-0.06, p<0.001). The ratio was also higher in patients with acute on chronic liver disease (1.11+/-0.39) compared to patients with cirrhosis (0.61+/-0.18, p<0.01). These differences were mainly due to low levels of linoleic acid and high levels of oleic acid in the patients with acute liver failure and acute on chronic liver disease. Two days of fat-free diet followed by infusion of glucose did not change this ratio (0.40+/-0.04 vs. 0.47+/-0.05, NS) in healthy controls. The essential fatty acid deficiency indicator eicosatrienoic acid was detectable in 2 out of 11 controls, in 5/10 with acute liver failure, in 7/7 with cirrhosis, and in 6/7 with acute on chronic liver disease.. Acute severe deterioration of liver function was associated with changes in the fatty acid composition of plasma phospholipids suggestive of essential fatty acid deficiency.

Topics: Acute Disease; Adult; Chronic Disease; Dietary Fats; Fatty Acids; Female; Glucose; Hepatic Encephalopathy; Humans; Linoleic Acid; Liver Cirrhosis; Liver Diseases; Liver Failure; Male; Middle Aged; Oleic Acid; Phospholipids; Reference Values

An experimental model of chronic pancreatitis was induced by a retrograde injection of a viscous solution consisting of zein-oleic acid-linoleic acid (0.05 ml/100 g body weight) into the rat pancreatic duct. Histologic and biochemical changes were investigated over a period of 6 months after induction of this model. The treated rats gained weight, but pancreatic weight decreased with time. Histologically, the widening of acinar lumen and cellular vacuolization occurred within 24 h at the parenchyma neighboring the small ducts filled with the injected solution. Degenerative parenchyma, interstitial edema, and inflammatory cell infiltration were pronounced 1 week later. Thereafter, duct-like tubular complex formation progressed, and the exocrine tissue exhibited marked atrophy of the gland with irregular fibrosis and fat replacement over a period of 6 months. Pancreatic contents of protein, amylase, DNA, and RNA markedly decreased, as did pancreatic weight, whereas hydroxyproline content increased. Oral administration of camostat did not affect pancreatic weight and contents of enzyme in this model. Urinary para-aminobenzoic acid (PABA) excretion in the BT-PABA test decreased to 54% at 6 weeks and 22% at 6 months. Although three quarters of pancreatic immunoreactive insulin (IRI) content was lost after 6 months, overt diabetes did not occur. The results suggest that an obstructive mechanism in the small ducts plays an important role in the genesis and development of chronic pancreatitis.

Topics: Amylases; Animals; Blood Glucose; Body Weight; Chronic Disease; Disease Models, Animal; Esters; Gabexate; Guanidines; Linoleic Acid; Male; Oleic Acid; Organ Size; Pancreas; Pancreatic Ducts; Pancreatitis; Protease Inhibitors; Rats; Rats, Wistar; Solutions; Survival Rate; Zein

Patients with chronic intestinal disorders causing malabsorption, nutritional losses through diarrhea, or catabolic illness would be expected to have essential fatty acid (EFA) deficiency (EFAD), but such deficiency has not been demonstrated in patients treated in accordance with the prevailing standard of care. We studied plasma fatty acid patterns of 56 reference or control subjects and 47 patients with chronic intestinal disorders (mostly Crohn's disease) using high-resolution capillary column gas-liquid chromatography. Patients exhibited a shift in fatty acid metabolism similar to that previously shown to be associated with EFAD. Compared with control subjects, patients had (1) decreased polyunsaturated fatty acid (PUFA) levels (43.7% v 50.4%, P < .0001), (2) increased monounsaturated fatty acid (MUFA) levels (25.8% v 22.0%, P < .0001), (3) higher ratios of mead (20:3 omega 9) to arachidonic (20:4 omega 6) acid (0.020 v 0.013, P < .04), and (4) lower concentrations of total (214 v 284 mg/dL, P < .01), saturated ([SFA] 63 v 75 mg/dL, P < .001), MUFA (56 v 63 mg/dL, P < .001), and PUFA (93 v 143 mg/dL, P < .001). Patients had metabolic shifts toward increased production of MUFA and an increased ratio of derivatives to precursors of omega 6 fatty acids, shifts that occur when cells are EFA-deficient. More than 25% of the patients had biochemical evidence of EFAD according to at least one criterion. Optimal diagnosis requires a concurrent evaluation of concentrations of fatty acids in plasma and in lipoproteins (percent fatty acids). On indices of EFA status that depend on percents, ratios, or concentrations of fatty acids or on the production of abnormal fatty acids, the patients were between patients with severe whole-body EFAD and healthy subjects, a state referred to as absolute EFA insufficiency. Patients with chronic intestinal disease should be evaluated for likely EFA deficiencies and imbalances, and treated with substantial amounts of supplements rich in EFAs, such as oral vegetable and fish oils, or intravenous lipids if necessary.

Topics: Adolescent; Adult; Analysis of Variance; Chronic Disease; Crohn Disease; Fatty Acids, Essential; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Gastrointestinal Diseases; Humans; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Multivariate Analysis; Reference Values

The role of oxygen derived free radicals or tissue lipid peroxides in the pathogenesis of chronic pancreatitis has not been established. To evaluate long-term effects of tissue lipid peroxides in the pathogenesis of chronic pancreatitis, we treated Wistar male rats with 2,2'-azo-bis-(2-amidino-propane) dihydrochloride (AAPH) and/or linoleic acid (LA) for 3 or 6 months. Rats were divided into eight groups. A: Saline-treated rats for 3 months as control, B: AAPH 40 mg/kgw intraperitoneally, twice a week for 3 months, C: LA 0.5 ml/kgw intraperitoneally, every other week for 3 months, D: AAPH and LA for 3 months, E: Saline-treated for 6 months, F: AAPH for 6 months, G: LA for 6 months, H: AAPH and LA for 6 months. The results were as follows: Lipid peroxide contents of the pancreas were elevated in groups: C, D, G and H. Histological examination revealed epithelial hyperplasia of large pancreatic ducts, vacuolization of ductal epithelium, intraepithelial neutrophilic infiltration, periductal mononuclear cell infiltration (ductulitis and peri-ductulitis), and sporadically in the lobules, destruction of acinar cells, neutrophilic infiltration and ductular proliferation in the same groups. These findings indicate that tissue damage was more severe in the pancreatic ducts than in the acinar cells, however no damage was seen in the endocrine pancreas. Vitamin E content of the pancreas was decreased in groups: B, C, D, F, G and H. Tissue glutathione peroxidase (GSH-Px) activity was increased in groups: D and H. Tissue catalase activity was increased in groups: D, G and H, but no change of superoxide dismutase (SOD) activity was seen in any of the groups. These results indicate that vitamin E may play the role of the main scavenger in the situation of a smaller dose of lipid peroxides, but when larger doses are administered, GSH-Px may play the main role as the scavenger in this experimental system.

Topics: Amidines; Animals; Chronic Disease; Free Radical Scavengers; Free Radicals; Glutathione Peroxidase; Linoleic Acid; Linoleic Acids; Lipid Peroxides; Male; Pancreas; Pancreatitis; Rats; Rats, Wistar

Topics: Animals; Chronic Disease; Disease Models, Animal; Drug Combinations; Exocrine Pancreatic Insufficiency; Injections; Linoleic Acid; Linoleic Acids; Male; Oleic Acids; Pancreatic Ducts; Rats; Rats, Inbred Strains; Solutions; Zein

Chronic pancreatic insufficiency (CPI) was induced in male Wistar rats by the injection of a zein-oleic acid-linoleic acid solution into their pancreaticobiliary ducts. Animals injected developed severe pancreatic atrophy with fibrosis and greater than 90% loss of pancreatic enzyme content. The animals also developed malabsorption of fat and bentiromide. Three weeks after the CPI lesion was induced, animals were randomized to receive cerulein 2 micrograms/kg twice daily subcutaneously or saline twice daily subcutaneously for 2 weeks. Cerulein significantly increased pancreatic trypsinogen (p less than 0.03), amylase (p less than 0.01), lipase (p less than 0.02), DNA (p less than 0.02), and RNA (p less than 0.01) content and improved fat and bentiromide malabsorption as compared to saline (p less than 0.05). We conclude that cerulein therapy can cause significant hyperplasia of pancreatic acinar parenchyma in an animal model of CPI and that this therapy can partially reverse malabsorption.

Topics: Animals; Ceruletide; Chronic Disease; Disease Models, Animal; Drug Combinations; Exocrine Pancreatic Insufficiency; Hyperplasia; Linoleic Acid; Linoleic Acids; Male; Oleic Acid; Oleic Acids; Pancreas; Rats; Rats, Inbred Strains; Zein