linoleic-acid and Cystic-Fibrosis

Nutrition is important in cystic fibrosis (CF) because the disease is associated with a higher energy consumption, special nutritional deficiencies, and malabsorption mainly related to pancreatic insufficiency. The clinical course with deterioration of lung function has been shown to relate to nutrition. Despite general recommendation of high energy intake, the clinical deterioration is difficult to restrain suggesting that special needs have not been identified and specified. It is well-known that the CF phenotype is associated with lipid abnormalities, especially in the essential or conditionally essential fatty acids. This review will concentrate on the qualitative aspects of fat metabolism, which has mainly been neglected in dietary fat recommendations focusing on fat quantity. For more than 60 years it has been known and confirmed that the patients have a deficiency of linoleic acid, an n-6 essential fatty acid of importance for membrane structure and function. The ratio between arachidonic acid and docosahexaenoic acid, conditionally essential fatty acids of the n-6 and n-3 series, respectively, is often increased. The recently discovered relations between the CFTR modulators and lipid metabolism raise new interests in this field and together with new technology provide possibilities to specify further specify personalized therapy.

Topics: Arachidonic Acid; Cystic Fibrosis; Docosahexaenoic Acids; Fatty Acids, Essential; Humans; Linoleic Acid

Adequate intake of nutrients such as essential fatty acids (EFA) are critical in cystic fibrosis (CF). The clinical course of deterioration of lung function in people with CF has been shown to relate to nutrition. Independent of the higher energy consumption and malabsorption due to pancreatic insufficiency, EFA deficiency is closely associated with the risk of pulmonary infection, the most significant pathology in CF. This review will focus on the EFA deficiency identified in people with CF, as well as the limited progress made in deciphering the exact metabolic pathways that are dysfunctional in CF. Specifically, people with CF are deficient in linoleic acid, an omega 6 fatty acid, and the ratio of arachidonic acid (omega 6 metabolite) and docosahexaenoic acid (omega 3 metabolite) is increased. Analysis of the molecular pathways in bronchial cells has identified changes in the enzymes that metabolise EFA. However, fatty acid metabolism primarily occurs in the liver, with EFA metabolism in CF liver not yet investigated, indicating that further research is required. Despite limited understanding in this area, it is well known that adequate EFA concentrations are critical to normal membrane structure and function, and thus are important to consider in disease processes. Novel insights into the relationship between CF genotype and EFA phenotype will be discussed, in addition to sex differences in EFA concentrations in people with CF. Collectively, investigating the specific effects of genotype and sex on fatty acid metabolism may provide support for the management of people with CF via personalised genotype- and sex-specific nutritional therapies.

Topics: Cystic Fibrosis; Disease Progression; Fatty Acids, Essential; Female; Genotype; Humans; Linoleic Acid; Male

While approximately 2000 mutations have been discovered in the gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR), only a small amount (about 10%) is associated with clinical cystic fibrosis (CF) disease. The discovery of the association between CFTR and the hyperactive epithelial sodium channel (ENaC) has raised the question of the influence of ENaC on the clinical CF phenotype. ENaC disturbance contributes to the pathological secretion, and overexpression of one ENaC subunit, the β-unit, can give a CF-like phenotype in mice with normal acting CFTR. The development of ENaC channel modulators is now in progress. Both CFTR and ENaC are located in the cell membrane and are influenced by its lipid configuration. Recent studies have emphasized the importance of the interaction of lipids and these proteins in the membranes. Linoleic acid deficiency is the most prevailing lipid abnormality in CF, and linoleic acid is an important constituent of membranes. The influence on sodium excretion by linoleic acid supplementation indicates that lipid-protein interaction is of importance for the clinical pathophysiology in CF. Further studies of this association can imply a simple clinical adjuvant in CF therapy.

Topics: Animals; Cell Membrane; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Sodium Channels; Humans; Linoleic Acid; Mice

Cystic fibrosis (CF) is a recessively inherited fatal disease that is the subject of extensive research and ongoing development of therapeutics targeting the defective protein, cystic fibrosis transmembrane conductance regulator (CFTR). Despite progress, the link between CFTR and clinical symptoms is incomplete. The severe CF phenotypes are associated with a deficiency of linoleic acid, which is the precursor of arachidonic acid. The release of arachidonic acid from membranes via phospholipase A

Topics: Arachidonic Acid; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Docosahexaenoic Acids; Humans; Inflammation; Linoleic Acid; Lipid Metabolism; Lung; Mucus

Despite identification twenty years ago of the gene responsible for cystic fibrosis transmembrane conductance regulator (CFTR), the protein defective in cystic fibrosis (CF), research of this monogenetic disease has not provided an explanation for the divergent symptoms, and a treatment breakthrough is still awaited. This review discusses different aspects of disturbances in lipid metabolism seen in CF. These include increased release of arachidonic acid (AA) from cell membrane phospholipids and a low status of linoleic and docosahexaenoic acids. Recent research has explored more complicated lipid associations. Disturbances in annexins and ceramides might act in concert to explain the impact on inflammation and AA release. The connections to CFTR and between the disturbances in essential fatty acid metabolism are reviewed. The metabolic interactions, some of which might be compensating, possibly explain the difficulties in understanding the fatty acid disturbances in relation to different symptoms and their relation to the defective CFTR.

Topics: Animals; Annexins; Arachidonic Acid; Ceramides; Cystic Fibrosis; Docosahexaenoic Acids; Fatty Acids; Humans; Linoleic Acid; Lipid Metabolism; Models, Biological

Topics: Adult; Cystic Fibrosis; Diet, Mediterranean; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Female; Humans; Linoleic Acid; Lipid Metabolism; Male

Since the discovery in 1929 that certain polyunsaturated fatty acids (PUFA) are essential for life and health, intense investigation has revealed the multiplicity of members in each of several families of PUFA, no two of which are equivalent. The quantified nutrient requirements for the essential dietary precursors of the two dominant families of PUFA have been estimated, and the general functions of these families are slowly becoming known. The PUFA are essential components of structural membrane lipids. The functions of the individual members are not yet differentiated, except as they act as precursors of synthesis of unique octadecanoid, eicosanoid, and docosanoid products of oxidation that have potent biological properties. The PUFA occur in animals and higher plants as ubiquitous and essential components of structural lipid that are in a dynamic equilibrium with the pool of dietary acyl groups. Many human diseases have been found to involve unique essential fatty acid (EFA) deficiencies or distortions of the normal equilibrium pattern. The equilibrium is influenced by the level of dietary intake or precursors, by the presence of competing essential and nonessential acyl groups, by nonoptimum intake of other essential nutrients, by hormonal effects, by drug therapy, and by other effects upon physiological condition. With the many variables already known to modulate or control the equilibrium, it should be possible with more precise understanding of each variable to shift abnormal equilibria in the direction of normalcy. This perhaps will be the next area of intensive investigation in this field of nutrition and metabolism.

Topics: Acrodermatitis; alpha-Linolenic Acid; Arachidonic Acid; Arachidonic Acids; Aspirin; Child; Crohn Disease; Cystic Fibrosis; DDT; Dicofol; Ethanol; Fatty Acids, Essential; Fatty Acids, Unsaturated; Female; Humans; Ichthyosis; Indomethacin; Isomerism; Linoleic Acid; Linoleic Acids; Linolenic Acids; Lipid Metabolism; Lipolysis; Liver Cirrhosis, Alcoholic; Models, Chemical; Myocardial Infarction; Protein-Energy Malnutrition; Reye Syndrome; Structure-Activity Relationship

Pancreatic enzyme therapy does not normalize dietary fat absorption in patients with cystic fibrosis and pancreatic insufficiency. Efficacy of LYM-X-SORB (LXS), an easily absorbable lipid matrix that enhances fat absorption, was evaluated in a 12-month randomized, double-blinded, placebo-controlled trial with plasma fatty acids (FA) and coefficient of fat absorption (CFA) outcomes. A total of 110 subjects (age 10.4 ± 3.0 years) were randomized. Total FA increased with LXS at 3 and 12 months (+1.58, +1.14 mmol/L) and not with placebo (P = 0.046). With LXS, linoleic acid (LA) increased at 3 and 12 months (+298, +175 nmol/mL, P ≤ 0.046), with a 6% increase in CFA (P < 0.01). LA increase was significant in LXS versus placebo (445 vs 42 nmol/mL, P = 0.038). Increased FA and LA predicted increased body mass index Z scores. In summary, the LXS treatment improved dietary fat absorption compared with placebo as indicated by plasma FA and LA and was associated with better growth status.

Topics: Adolescent; Child; Child Nutritional Physiological Phenomena; Cystic Fibrosis; Dietary Fats; Exocrine Pancreatic Insufficiency; Female; Humans; Intestinal Absorption; Linoleic Acid; Lipids; Male; Treatment Outcome

Airway inflammation is a significant contributor to the morbidity of cystic fibrosis (CF) disease. One feature of this inflammation is the production of oxygenated metabolites, such as prostaglandins. Individuals with CF are known to have abnormal metabolism of fatty acids, typically resulting in reduced levels of linoleic acid (LA) and docosahexaenoic acid (DHA).. This is a randomized, double-blind, cross-over clinical trial of DHA supplementation with endpoints of plasma fatty acid levels and prostaglandin E metabolite (PGE-M) levels. Patients with CF age 6-18 years with pancreatic insufficiency were recruited. Each participant completed 3 four-week study periods: DHA at two different doses (high dose and low dose) and placebo with a minimum 4 week wash-out between each period. Blood, urine, and exhaled breath condensate (EBC) were collected at baseline and after each study period for measurement of plasma fatty acids as well as prostaglandin E metabolites.. Seventeen participants were enrolled, and 12 participants completed all 3 study periods. Overall, DHA supplementation was well tolerated without significant adverse events. There was a significant increase in plasma DHA levels with supplementation, but no significant change in arachidonic acid (AA) or LA levels. However, at baseline, AA levels were lower and LA levels were higher than previously reported for individuals with CF. Urine PGE-M levels were elevated in the majority of participants at baseline, and while levels decreased with DHA supplementation, they also decreased with placebo.. Urine PGE-M levels are elevated at baseline in this cohort of pediatric CF patients, but there was no significant change in these levels with DHA supplementation compared to placebo. In addition, baseline plasma fatty acid levels for this cohort showed some difference to prior reports, including higher levels of LA and lower levels of AA, which may reflect changes in clinical care, and consequently warrants further investigation.

Topics: Adolescent; Arachidonic Acid; Child; Cross-Over Studies; Cystic Fibrosis; Dietary Supplements; Docosahexaenoic Acids; Double-Blind Method; Fatty Acids; Female; Humans; Linoleic Acid; Male; Pilot Projects; Prospective Studies; Prostaglandins; Treatment Outcome

Chronic inflammation plays a major role in lung deterioration in cystic fibrosis (CF) patients and anti-inflammatory strategies have beneficial effects. To study the changes seen after a one-year course of low-dose dietary supplements with a mixture of fatty acids in adult patients with CF in chronic inflammation, pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), quality of life and anthropometric parameters.. Seventeen adult subjects with CF received 324 mg of eicosapentaenoic, 216 mg of docosahexaenoic, 480 mg of linoleic and 258 mg of gammalinolenic acid daily. We assessed inflammation markers, spirometry parameters, number and severity of respiratory exacerbations, antibiotic consumption, quality of life (St George's QoL), anthropometric parameters and serum phospholipid fatty acid composition.. At the end of the treatment period TNF alpha levels fell significantly and its soluble receptors (60 and 80) rose significantly. Levels of IgG and IgM anti-oxidized LDL antibodies fell significantly. Spirometry improved significantly. Annual respiratory exacerbations and days of antibiotic treatment fell significantly. The improvement in QoL was not significant. Serum levels of docosahexaenoic, total omega-3 and linoleic acid rose significantly and more favourable profiles were seen in monoenoic acids, arachidonic acid and the arachidonic/docosahexaenoic ratio. The fat-free mass and hand grip dynamometry improved significantly.. Low-dose supplements of n-3 and gammalinolenic fatty acids over a long period (one year) appears to improve pulmonary status (lung function, respiratory exacerbations and antibiotic consumption), inflammatory and anthropometric parameters in adults with CF.

Topics: Adolescent; Adult; Anthropometry; Autoantibodies; Body Composition; Cystic Fibrosis; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; gamma-Linolenic Acid; Humans; Inflammation; Linoleic Acid; Lipoproteins, LDL; Male; Quality of Life; Receptors, Tumor Necrosis Factor; Respiratory Function Tests; Respiratory Tract Infections; Severity of Illness Index; Sputum; Tumor Necrosis Factor-alpha; Vitamin E; Young Adult

Patients with cystic fibrosis who have steatorrhea frequently are underweight and have essential fatty acid (EFA) depletion, which is associated with a poor clinical course. It has been stated that poor EFA status is difficult to correct in patients with cystic fibrosis, and an impaired EFA metabolism with reduced synthesis of long-chain polyunsaturated fatty acids has been proposed. In this study, the effects of an oral energy supplement rich in linoleic acid were investigated in patients with cystic fibrosis who had a body weight below 95% of normal for height.. Thirty-six patients (16 girls) more than 4 years of age were randomized either to a control group (n = 20, age 13.3 +/- 3.8 years, mean +/- SD) receiving intensive dietary counseling only, or an intervention group (n = 16, age, 10.4 +/- 4.3 years) treated for 3 months with dietary counseling plus 628 +/- 254 mL (= kcal) per day of an energy supplement rich in fat (31% of energy) and linoleic acid (16% of energy).. In contrast to the control group, the patients with supplemented diets achieved significant increases of energy intake (2189 +/- 731 kcal/day vs. 2733 +/- 762 kcal/day), weight for height (82.8% +/- 8.6% vs. 84.8% +/- 9.6% of normal), and body fat (5.1 +/- 1.7 kg vs. 5.8 +/- 2.2 kg) as well as the initially low values of plasma phospholipid linoleic acid (11.8% +/- 1.1% vs. 17.6% +/- 1.6% of total phospholipid fatty acids) and its main metabolite arachidonic acid (4.4% +/- 0.4% vs. 5.9% +/- 0.3%).. Patients with cystic fibrosis with low body weight and poor EFA status benefit from EFA-rich energy supplements and can synthesize arachidonic acid from the precursor linoleic acid.

Topics: Adolescent; Body Weight; Celiac Disease; Child; Cystic Fibrosis; Dietary Supplements; Energy Intake; Fatty Acids, Essential; Female; Humans; Linoleic Acid; Male

Pancreatic enzyme replacement therapy frequently fails to correct intestinal fat malabsorption completely in cystic fibrosis (CF) patients. The reason for this failure is unknown.. We investigated whether fat malabsorption in CF patients treated with pancreatic enzymes is caused by insufficient lipolysis of triacylglycerols or by defective intestinal uptake of long-chain fatty acids.. Lipolysis was determined on the basis of breath 13CO2 recovery in 10 CF patients receiving pancreatic enzyme replacement therapy after they ingested 1.3-distearoyl,2[1-13C]octanoyl glycerol ([13C]MTG). Intestinal uptake of long-chain fatty acids was determined by analyzing plasma [13C]linoleic acid ([13C]LA) concentrations after patients ingested [13C]LA. For 3 d, dietary intakes were recorded and feces were collected.. Fecal fat excretion ranged from 5.1 to 27.8 g/d (mean+/-SD: 11.1+/-7.0 g/d) and fat absorption ranged from 79% to 93% (89+/-5%). There was no relation between breath 13CO2 recovery and dietary fat absorption (r = 0.04) after ingestion of [13C]MTG. In contrast, there was a strong relation between 8-h plasma [13C]LA concentrations and dietary fat absorption (r = 0.88, P < 0.001).. Our results suggest that continuing fat malabsorption in CF patients receiving enzyme replacement therapy is not likely due to insufficient lipolytic enzyme activity, but rather to incomplete intraluminal solubilization of long-chain fatty acids, reduced mucosal uptake of long-chain fatty acids, or both.

Topics: Adolescent; Child; Cystic Fibrosis; Dietary Fats; Fatty Acids; Feces; Female; Humans; Intestinal Absorption; Intestinal Mucosa; Linoleic Acid; Lipolysis; Malabsorption Syndromes; Male; Nutrition Policy; Pancreatic Extracts; Triglycerides

Essential fatty acid deficiency as a result of inadequate linoleic acid impairs growth in healthy infants and is common in infants with malabsorption due to cystic fibrosis (CF). We investigated the effect of dietary linoleic acid intake on the growth of infants with CF. In this study, predigested formula preparations A and B, with linoleic acid contents of 12% and 7% of energy, respectively, were fed before and after 1989 to infants enrolled in the evaluation and treatment protocol of the Wisconsin CF Neonatal Screening Project. Outcome was assessed from height-for-age (HAZ) and weight-for-age (WAZ) Z scores on follow-up exams during the first year. Baseline characteristics did not differ significantly between groups A (n = 43) and B (n = 33). At diagnosis, 53% of the enrolled infants (n = 76) showed low plasma linoleic acid concentrations and 22% had a high ratio of triene to tetraene. After correcting for the effect of potentially confounding variables, we found that HAZ (by .27, P < 0.05) and WAZ (by 0.26, P = 0.081) were higher in group A than in group B. This occurred despite a significantly higher energy intake in group B. This difference was most pronounced between 6 and 9 mo of age. Our results suggest that a high linoleic acid content in formula benefits infants with CF because it optimizes nutrition, growth, and feeding efficiency.

Topics: Age Factors; Body Height; Body Weight; Cystic Fibrosis; Deficiency Diseases; Energy Intake; Fatty Acids, Essential; Female; Growth; Growth Disorders; Humans; Infant; Infant Food; Infant, Newborn; Linoleic Acid; Linoleic Acids; Longitudinal Studies; Male; Prevalence; Wisconsin

Fatty acid compositions of the major serum lipid classes from 43 cystic fibrosis (CF) homozygotes (CF patients), 36 obligate heterozygotes (parents of CF patients) and 34 controls were determined by capillary gas chromatography. Fatty acid compositions of the homozygote CF patients were skewed in the direction of relative essential fatty acid deficiency in comparison with the controls. Less pronounced, but similar deviations from normal, were observed in the heterozygotes. Homozygotes with normal fatty acid compositions and heterozygotes with considerably disturbed fatty acid profiles were found.

Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Fatty Acids; Female; Heterozygote; Homozygote; Humans; Linoleic Acid; Linoleic Acids; Male; Parents; Phospholipids

Topics: Animals; Arachidonic Acid; Cystic Fibrosis; Disease Models, Animal; Docosahexaenoic Acids; Female; Linoleic Acid; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CFTR; Mice, Knockout

Ivacaftor has produced significant improvement in certain individuals with cystic fibrosis (CF), though the full metabolic effects of treatment remain unknown. Abnormalities in fatty acid metabolism have previously been shown to be a characteristic of CFTR dysfunction. We hypothesized that as a reflection of this clinical improvement, ivacaftor would improve plasma fatty acid levels and decrease urine prostaglandin E metabolite levels.. This study analyzed plasma fatty acid levels and urine prostaglandin E metabolites (PGE-M) in 40 subjects with CF participating in the G551D observational (GOAL) study who demonstrated response to the medication by a significant decrease in sweat Cl levels. Paired samples were analyzed before and after 6months of ivacaftor treatment.. Linoleic acid and docosahexaenoic acid levels, which are typically low in individuals with CF, did not significantly increase with ivacaftor treatment. However, arachidonic acid levels did decrease with ivacaftor treatment and there was a significant decrease in the arachidonic acid metabolite PGE-M as measured in the urine [median: before treatment 17.03ng/mg Cr; after treatment 9.06ng/mg Cr; p<0.001]. Furthermore, there were fatty acid age differences observed, including pediatric participants having significantly greater linoleic acid levels at baseline.. Ivacaftor reduces inflammatory PGE without fully correcting the plasma fatty acid abnormalities of CF. Age-related differences in fatty acid levels were observed, that may be a result of other clinical factors, such as diet, clinical care, or drug response.

Topics: Adult; Aminophenols; Arachidonic Acid; Child; Chloride Channel Agonists; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Monitoring; Fatty Acids, Monounsaturated; Female; Humans; Inflammation Mediators; Linoleic Acid; Lipid Metabolism; Male; Mutation; Pilot Projects; Prostaglandins E; Quinolones

Children with cystic fibrosis (CF) and pancreatic insufficiency (PI) are at risk for fatty acid (FA) abnormalities and essential FA deficiency, with low linoleic acid (LA) and docosahexaenoic acid (DHA) concentrations and abnormal triene:tetraene (T:T) and arachidonic acid (AA):DHA ratios. The aim of the article was to determine whether type of dietary fat predicted serum LA, DHA, T:T, and AA:DHA ratios in subjects with CF and PI as compared to an unaffected comparison group.. Serum FA concentrations were assessed by capillary gas-liquid chromatography (mol%) and dietary intake by 7-day weighed food records; the 3-day coefficient of fat absorption was calculated. Total energy intake was expressed in kilocalories.. A total of 65 subjects with CF and PI (8.4 ± 1.0 years, 32 girls) and 22 controls (8.5 ± 1.1 years, 13 girls) were included. Despite greater energy, saturated fat, and LA intake, the subjects with CF had lower serum LA and DHA and higher T:T and AA:DHA than those in the comparison group. Dietary total fat, monounsaturated fatty acid (MUFA), polyunsaturated fatty acid (PUFA), LA, total ω 6 polyunsaturated fatty acid (Tω6PUFA), and α-linolenic acid (ALA) intake positively predicted serum LA concentration. MUFA, total ω 3 polyunsaturated fatty acid (Tω3PUFA), and ALA intake positively predicted serum DHA concentration. Total dietary fat, MUFA, PUFA, Tω3PUFA, LA, and ALA intake negatively predicted serum T:T. ALA and Tω3PUFA intake negatively predicted serum AA:DHA.. Dietary fat patterns influenced serum LA, DHA, T:T, and AA:DHA in children with CF and PI. These data suggest that changes in dietary practices may result in FA profiles associated with improved clinical outcomes.

Topics: alpha-Linolenic Acid; Arachidonic Acid; Child; Cystic Fibrosis; Diet; Dietary Fats; Docosahexaenoic Acids; Energy Intake; Exocrine Pancreatic Insufficiency; Female; Humans; Linoleic Acid; Male; Nutritional Status

Cystic fibrosis (CF) patients display a fatty acid imbalance characterized by low linoleic acid levels and variable changes in arachidonic acid. This led to the recommendation that CF patients consume a high-fat diet containing >6% linoleic acid. We hypothesized that increased conversion of linoleic acid to arachidonic acid in CF leads to increased levels of arachidonate-derived proinflammatory metabolites and that this process is exacerbated by increasing linoleic acid levels in the diet. To test this hypothesis, we determined the effect of linoleic acid supplementation on downstream proinflammatory biomarkers in two CF models: 1) in vitro cell culture model using 16HBE14o(-) sense [wild-type (WT)] and antisense (CF) human airway epithelial cells; and 2) in an in vivo model using cftr(-/-) transgenic mice. Fatty acids were analyzed by gas chromatography-mass spectrometry (GC/MS), and IL-8 and eicosanoids were measured by ELISA. Neutrophils were quantified in bronchoalveolar lavage fluid from knockout mice following linoleic acid supplementation and exposure to aerosolized Pseudomonas LPS. Linoleic acid supplementation increased arachidonic acid levels in CF but not WT cells. IL-8, PGE(2), and PGF(2α) secretion were increased in CF compared with WT cells, with a further increase following linoleic acid supplementation. cftr(-/-) Mice supplemented with 100 mg of linoleic acid had increased arachidonic acid levels in lung tissue associated with increased neutrophil infiltration into the airway compared with control mice. These findings support the hypothesis that increasing linoleic acid levels in the setting of loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to increased arachidonic acid levels and proinflammatory mediators.

Topics: Animals; Arachidonic Acid; Biomarkers; Bronchoalveolar Lavage Fluid; Cell Line; Cystic Fibrosis; Dietary Supplements; Disease Models, Animal; Eicosanoids; Fatty Acids; Humans; Inflammation; Interleukin-8; Linoleic Acid; MAP Kinase Signaling System; Mice; Mice, Inbred CFTR; Mice, Knockout; Mice, Transgenic; Pseudomonas aeruginosa; Respiratory Mucosa

Topics: Adolescent; Adult; Animals; Cystic Fibrosis; Dietary Supplements; Humans; Linoleic Acid; Mice

An imbalance in (n-6)/(n-3) PUFA has been reported in cystic fibrosis (CF) patients. Glycerophospholipids enriched in docosahexaenoic acid (GPL-DHA) have been shown to regulate the (n-6)/(n-3) fatty acid ratio in the elderly. Here, we tested the effect of GPL-DHA supplementation on PUFA status in F508del homozygous CF mice. GPL-DHA liposomes were administrated by gavage (60 mg DHA/kg daily, i.e. at maximum 1.4 mg DHA/d) to 1.5-mo-old CF mice (CF+DHA) and their corresponding wild-type (WT) homozygous littermates (WT+DHA) for 6 wk. The PUFA status of different tissues was determined by GC and compared with control groups (CF and WT). There was an alteration in the (n-6) PUFA pathway in several CF-target organs in CF compared with WT mice, as evidenced by a higher level of arachidonic acid (AA) in membrane phospholipids or whole tissue (21 and 39% in duodenum-jejunum, 32 and 38% in ileum, and 19 and 43% in pancreas). Elevated AA levels were associated with lower linoleic acid (LA) and higher dihomo-gamma-linolenic acid levels. No DHA deficiency was observed. GPL-DHA treatment resulted in different PUFA composition changes depending on the tissue (increase in LA, decrease in elevated AA, DHA increase, increase in (n-6)/(n-3) fatty acid ratio). However, the DHA/AA ratio consistently increased in all tissues in CF+DHA and WT+DHA mice. Our study demonstrates the effectiveness of an original oral DHA formulation in counter-balancing the abnormal (n-6) fatty acid metabolism in organs of CF mice when administrated at a low dose and highlights the potential of the use of GPL-DHA as nutritherapy for CF patients.

Topics: Animals; Arachidonic Acid; Cell Membrane; Cystic Fibrosis; Dietary Supplements; Disease Models, Animal; Docosahexaenoic Acids; Fatty Acids; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Glycerophospholipids; Humans; Intestinal Mucosa; Intestines; Linoleic Acid; Lipids; Lung; Mice; Mice, Inbred Strains; Pancreas; Phospholipids; Sequence Deletion

Children with cystic fibrosis (CF) and pancreatic insufficiency (PI) are at increased risk for essential fatty acid (EFA) deficiency.. To investigate serum markers of EFA status in children with CF and PI and their association with growth, body composition, and lung function.. Serum phospholipid fatty acid, growth, and forced expiratory volume at 1 second (FEV1, percentage predicted) status were assessed at baseline and 12 months in 77 children with CF and PI, 7 to 10 years old. Longitudinal mixed-effects models were used to compare associations of the triene:tetraene ratio (ratio of eicosatrienoic acid to arachidonic acid) and serum linoleic acid (as a molar percentage of total serum phospholipid fatty acids, or mol%) with the clinical outcomes. Controls for serum fatty acid were 23 healthy white age- and sex-matched children.. Children with CF and PI had higher median triene:tetraene ratio and lower linoleic acid than healthy controls. Depending on the triene:tetraene ratio cutoff point used (0.04 or 0.02), either 17% or 52% of the children with CF had EFA deficiency, respectively. Only linoleic acid was significantly and positively associated with z scores for weight, height, body mass index, upper arm muscle area, and FEV1 at baseline. Children with linoleic acid at 21 mol% or higher had significantly better growth and pulmonary status than those with lower concentrations.. Serum phospholipid linoleic acid at 21 mol% or higher was associated with better growth, body composition, and FEV1. No clinical outcome associations were found with the triene:tetraene ratio. These findings suggest that linoleic acid concentration was a more clinically relevant biomarker of EFA status than the triene:tetraene ratio in children with CF and PI. Further research is warranted to validate this specific percentage of linoleic acid cutoff point as a new recommendation for clinical use.

Topics: Adipose Tissue; Biomarkers; Body Composition; Body Mass Index; Body Weight; Child; Cystic Fibrosis; Energy Intake; Fatty Acids, Essential; Female; Genotype; Humans; Linoleic Acid; Male; Phospholipids; Reference Values

Cystic fibrosis (CF) is associated with fatty acid alterations characterized by low linoleic and docosahexaenoic acid. It is not clear whether these fatty acid alterations are directly linked to cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction or result from nutrient malabsorption. We hypothesized that if fatty acid alterations are a result of CFTR dysfunction, those alterations should be demonstrable in CF cell culture models. Two CF airway epithelial cell lines were used: 16HBE, sense and antisense CFTR cells, and C38/IB3-1 cells. Wild-type (WT) and CF cells were cultured in 10% fetal bovine serum (FBS) or 10% horse serum. Fatty acid levels were analyzed by GC-MS. Culture of both WT and CF cells in FBS resulted in very low linoleic acid levels. When cells were cultured in horse serum containing concentrations of linoleic acid matching those found in human plasma, physiological levels of linoleic acid were obtained and fatty acid alterations characteristic of CF tissues were then evident in CF compared with WT cells. Kinetic studies with radiolabeled linoleic acid demonstrated in CF cells increased conversion to longer and more-desaturated fatty acids such as arachidonic acid. In conclusion, these data demonstrate that CFTR dysfunction is associated with altered fatty acid metabolism in cultured airway epithelial cells.

Topics: Animals; Antisense Elements (Genetics); Bronchi; Cell Count; Cells, Cultured; Culture Media; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Cells; Fatty Acids; Humans; Linoleic Acid; Mice

Specific fatty acid alterations have been described in the blood and tissues of cystic fibrosis (CF) patients. The principal alterations include decreased levels of linoleic acid (LA) and docosahexaenoic acid (DHA). We investigated the potential mechanisms of these alterations by studying the cellular uptake of LA and DHA, their distribution among lipid classes, and the metabolism of LA in a human bronchial epithelial cell model of CF. CF (antisense) cells demonstrated decreased levels of LA and DHA compared with wild type (WT, sense) cells expressing normal CFTR. Cellular uptake of LA and DHA was higher in CF cells compared with WT cells at 1 h and 4 h. Subsequent incorporation of LA and DHA into most lipid classes and individual phospholipids was also increased in CF cells. The metabolic conversion of LA to n-6 metabolites, including 18:3n-6 and arachidonic acid, was upregulated in CF cells, indicating increased flux through the n-6 pathway. Supplementing CF cells with DHA inhibited the production of LA metabolites and corrected the n-6 fatty acid defect. In conclusion, the evidence suggests that low LA level in cultured CF cells is due to its increased metabolism, and this increased LA metabolism is corrected by DHA supplementation.

Topics: Cells, Cultured; Cystic Fibrosis; Docosahexaenoic Acids; Humans; Linoleic Acid; Respiratory Mucosa

Topics: Adolescent; Adult; Arachidonic Acid; Bile Acids and Salts; Child; Child, Preschool; Cystic Fibrosis; Docosahexaenoic Acids; Eicosapentaenoic Acid; Energy Intake; Fatty Acids, Unsaturated; Forced Expiratory Volume; Humans; Linoleic Acid; Lung; Nutritional Status; Phospholipids; Reference Values; Respiratory Function Tests

An association has been reported between alterations in fatty acid metabolism and cystic fibrosis (CF). We hypothesized that these alterations are specific for a particular lipid component(s) and are the result of a specific metabolic defect. The different lipid classes were examined for fatty acid changes by using pancreatic homogenates and primary cultures of pancreatic acini from cftr(-/-) (CF) and wild-type mice. Lipid classes and phospholipids were separated by aminopropyl column chromatography and high-performance liquid chromatography, and fatty acid methyl esters were analyzed. The results indicate that in CF mice (1) linoleate was decreased in phospholipids but not in neutral lipids; (2) there was an increase in dihomo-gamma-linolenate and in docosapentaenoate, the terminal fatty acid of the n-6 pathway, in total lipids and total phospholipids, but not in the neutral lipid class; and (3) the docosapentaenoate (n-6)/docosahexaenoate (n-3) ratio was significantly elevated in neutral phospholipids. This suggests an enhanced flux through the n-6 pathway beyond arachidonate. This study provides a more in-depth understanding of the fatty acid alterations found in CF, as reflected by the cftr(-/-) mouse model.

Topics: Animals; Cells, Cultured; Chromatography, High Pressure Liquid; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Linoleic Acid; Lipids; Mice; Mice, Inbred CFTR; Pancreas; Phospholipids

Topics: Arachidonic Acid; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Docosahexaenoic Acids; Humans; Linoleic Acid; Mutation

To determine if the serum phospholipid fatty acid pattern in patients with cystic fibrosis (CF) was related to the major cystic fibrosis transmembrane conductance regulator gene mutations.. Patients with CF (n = 110) aged 3 months to 56 years were studied. Serum samples were analyzed for phospholipid fatty acid with gas-liquid chromatography, and cystic fibrosis transmembrane conductance regulator mutations were determined with standard methods.. Patients with CF had significantly lower molar percentages of linoleic acid and docosahexaenoic acid in the serum phospholipid than healthy controls (mean +/- standard deviation, 20.3 +/- 4.5 and 2.6 +/- 0.9 vs 22.4 +/- 2.2 and 3.1 +/- 0.7, respectively; P <.001). Palmitoleic and oleic acids were significantly increased (P <.001) but arachidonic acid was not different from controls. Homozygotes for DeltaF508 and heterozygotes/homozygotes for 394delTT showed significantly lower concentrations of linoleic acid and docosahexaenoic acid than the other groups. Low values were not correlated to anthropometric data or lung function. Patients with pancreatic insufficiency showed similar differences to those with sufficient pancreatic function, reflecting the different genotypes.. Serum concentrations of linoleic acid and docosahexaenoic acid were significantly lower in patients with severe cystic fibrosis transmembrane conductance regulator mutations, suggesting an association between the basic defect and abnormal essential fatty acid metabolism in CF patients.

Topics: Adolescent; Adult; Child; Child, Preschool; Cystic Fibrosis; Docosahexaenoic Acids; Fatty Acids, Essential; Genotype; Humans; Infant; Linoleic Acid; Middle Aged; Phospholipids; Sweden

Topics: Cystic Fibrosis; Dietary Fats; Humans; Intestinal Absorption; Linoleic Acid; Malabsorption Syndromes; Pancreatic Extracts

The urinary excretion rate (ng/h/1.73 m2) of prostanoids was determined with a capillary gas-liquid chromatographic mass spectrometric method in 19 patients with cystic fibrosis (CF) aged 1-29 years. Patients with CF showed an increased excretion of prostaglandin E2 metabolites (PGE-M) and thromboxane B2 and its metabolites at all ages. An imbalance in the excretion pattern of thromboxane B2 metabolites also suggested a relative impairment of beta-oxidation. There was no increased excretion of dinor-6-keto-PGF1 alpha, indicating normal prostacyclin biosynthesis. No correlation was found to genotype, clinical score, lung function or bacterial colonization but a significant negative relation was found between the main prostanoids in the urine and serum phospholipid levels of essential fatty acids. The results show that, contrary to the generally accepted decrease of prostanoid excretion in essential fatty acid deficiency, patients with CF increase their production parallel to the development of the deficiency. Since prostanoid synthesis is rate limited by arachidonic acid release, our data support a previously presented hypothesis about a pathological regulation of the release of arachidonic acid in CF.

Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Cystic Fibrosis; Dinoprostone; Epoprostenol; Fatty Acids; Female; Humans; Infant; Linoleic Acid; Linoleic Acids; Male; Phospholipids; Prostaglandins; Thromboxane A2; Thromboxane B2

This study investigated whether making epithelial cell membranes impermeable to Cl- movement affects incorporation of fatty acids into membrane constituents. Epithelial cells were isolated from human nasal polyps, cultured for 5-7 days, and used to test the effect of anthracene 9-carboxylate (9-AC), known to inhibit Cl- conductance across the epithelial membrane, on the incorporation and desaturation of [1-14C]linoleic acid (C18:2,n-6) in experiments of up to 4 h duration. 9-AC (5 mM) reduced C18:2,n-6 incorporation into phospholipid by 60-70%, and increased incorporation of C18:2,n-6 into triacylglycerol by 50-100%. The decrease in C18:2,n-6 incorporation into phospholipid was rapid and dependent on the concentration of 9-AC. Substitution of extracellular Cl- with gluconate significantly decreased C18:2,n-6 incorporation into phospholipid, suggesting that the effect of 9-AC may occur by inhibiting Cl- conductance. Lipid analysis of cells exposed to 50 microM-C18:2 revealed that, as a consequence of the effect of 9-AC, the level of C18:2,n-6 in cell membrane phospholipid was significantly lowered. The relative rate of C18:2,n-6 desaturation was not apparently changed by 9-AC. These data suggest that Cl- conductance may play a role in fatty acid incorporation into epithelial cell membrane phospholipids.

Topics: Amiloride; Anthracenes; Cells, Cultured; Chloride Channels; Chlorides; Cystic Fibrosis; Electric Conductivity; Epithelium; Fatty Acids; Humans; Kinetics; Linoleic Acid; Linoleic Acids; Membrane Proteins; Nasal Mucosa; Nasal Polyps; Phospholipids; Triglycerides; Verapamil

Vitamin E status was assessed in 22 patients with cystic fibrosis and 9 controls by measuring concentrations of the vitamin, vitamin E:lipid ratios and peroxide-induced haemolysis in plasma and erythrocytes. For a given concentration of plasma or erythrocyte alpha-tocopherol, erythrocytes of patients with cystic fibrosis were more susceptible to peroxide-induced haemolysis than controls. This susceptibility should be countered by supplementation with vitamin E to maintain higher than normal concentrations of circulating alpha-tocopherol-greater than 4.8 mmol alpha-tocopherol/mol cholesterol.

Topics: Adolescent; Arachidonic Acid; Child; Child, Preschool; Cholesterol; Cystic Fibrosis; Erythrocytes; Female; Hemolysis; Humans; Linoleic Acid; Linoleic Acids; Lipids; Male; Peroxides; Triglycerides; Vitamin E

A study of plasmatic fatty acids was carried out on a group of paediatric patients suffering from cystic fibrosis. These data have been compared with those obtained by others authors. High levels of saturated fatty acids and a reduction of polyunsaturates have been found. The ratio of eicosatrienoic acid to arachidonic acid is high in this group of patients, which indicates a certain lack of essential fatty acids.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Arachidonic Acid; Arachidonic Acids; Child; Child, Preschool; Cystic Fibrosis; Dietary Fats; Fatty Acids; Female; Humans; Infant; Linoleic Acid; Linoleic Acids; Male; Nutrition Disorders

Fatty acid composition of plasma lipids was analyzed in malnourished cystic fibrosis patients undergoing 6 months of nutritional rehabilitation. There were three males and five females (mean age 15.1 yr); five patients had pancreatic insufficiency. Nutritional rehabilitation in seven of eight patients was accomplished by nocturnal nasogastric infusion of a high-carbohydrate semisynthetic diet, in addition to daily meals. One patient received high-energy food supplements as snacks in addition to regular meals. All patients were moderately to severely malnourished on entry to the study and showed significant improvement over the 6 months in (means +/- SE) energy intake (96 +/- 8.0 to 126 +/- 11% recommended daily allowance) and body composition (80 +/- 4 to 90 +/- 4% ideal body weight). Daily intakes of linoleic acid were not significantly different before or during nutritional rehabilitation either as an absolute amount (383 +/- 45 to 557 +/- 124 mg/kg/day) or as a percentage of total calories (4.50 +/- 0.40 to 4.73 +/- 0.14%). In comparison to the controls, the relative percentage of plasma cholesterol ester fatty acids of the CF patients on entry into the study showed a marked decrease of linoleic acid (52.7 +/- 1.0 versus 42.3 +/- 2.7%) with elevated palmitoleic (2.34 +/- 0.2 versus 5.64 +/- 0.7%) and oleic (18.7 +/- 1.0 versus 25.2 +/- 1.4%) acids; a pattern consistent with essential fatty acid deficiency. However, this pattern is not truly characteristic of a pure linoleic acid deficiency as the metabolites of linoleic acid were not decreased.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Cystic Fibrosis; Dietary Fats; Dietary Proteins; Energy Intake; Fatty Acids; Fatty Acids, Essential; Feces; Female; Food, Fortified; Humans; Linoleic Acid; Linoleic Acids; Lipids; Male; Zinc

Patients with cystic fibrosis (CF) and pancreatic insufficiency usually have decreased linoleic and increased oleic, palmitoleic and eicosatrienoic (20:3 omega 9) acids compared to normal values of blood and tissue lipids. These changes are consistent with early essential fatty acid deficiency and are observed despite the regular use of exogenous pancreatic enzyme supplementation. As part of a study to determine the relative role of malabsorption as the etiology for the altered fatty acid status, the change in total plasma fatty acids and in area percent of plasma linoleic acid was determined in CF patients and control subjects following the ingestion of various lipid supplements, including two safflower oil preparations and two structured lipid preparations. Fasting subjects consumed 36 g of lipid in a milkshake containing 15 g of protein and 45 g of carbohydrate. Plasma samples obtained 0, 2, 4, 6 and 8 hr after the meal showed that the CF patients absorbed all preparations when administered with their regular dose of pancreatic enzyme supplement. Comparison of the patterns of increase for total plasma fatty acids and area percent of plasma linoleic acid following the administration of the different lipid supplements in CF patients and control subjects suggests that malabsorption alone is not the cause of the abnormal fatty acid composition in the lipids of CF patients and that increased caloric intake along with consumption of adequate amounts of linoleic acid should improve the linoleic acid status of CF patients; there may be selectively increased metabolism of certain fatty acids from the ingested lipids in the relatively malnourished CF patient compared to control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Cystic Fibrosis; Fatty Acids; Female; Humans; Intestinal Absorption; Linoleic Acid; Linoleic Acids; Male; Plant Oils; Safflower Oil; Triglycerides

A semi-synthetic diet (Vivonex) was administered via nasogastric tube to three cystic fibrosis patients with pancreatic exocrine deficiency for 14 days to gain weight. Dietary essential fatty acids were provided as safflower oil, which constituted 1.3% of total calories. Plasma and red blood cells were analyzed for the content and composition of lipids at the start of the diet and at days 7 and 14 of the dietary period, and the results were correlated with the morphology of the cells. Feeding Vivonex to the patients led to an essential fatty acid deficiency, which was manifested in a 50% decrease in the linoleic acid content of the phosphatidylcholine of plasma and red blood cells at days 7 and 14 and in a 20% decrease in the linoleic acid content of red cell phosphatidylethanolamine at day 14. There was no significant alteration in the levels or composition of the other phospholipid classes and in the free cholesterol/phospholipid ratio. The decrease in the linoleic acid content of the erythrocytes was accompanied by a dramatic increase in the proportion of cells as echinocytes. We conclude that restricted linoleic acid availability in cystic fibrosis patients causes a change in red blood cell shape either directly by decreasing the linoleoylphosphatidylcholine content of the membrane or indirectly by affecting enzyme activity.

Topics: Adolescent; Cystic Fibrosis; Dietary Fats; Erythrocyte Membrane; Erythrocytes; Erythrocytes, Abnormal; Fatty Acids; Fatty Acids, Essential; Food, Formulated; Humans; Linoleic Acid; Linoleic Acids; Lipids; Membrane Lipids; Microscopy, Electron; Phosphatidylcholines; Phosphatidylethanolamines

Fatty acids were measured by gas chromatography in lipid extracts of plasma and tissues obtained from three categories of 46 patients with cystic fibrosis. Low levels of the major essential fatty acid linoleate were found in plasma total lipids of patients who had malabsorption but not in those without evidence of steatorrhea. Circulating arachidonic acid was only slightly decreased, and the unusual triene reflecting pathologically altered fatty acid metabolism (20:3 omega 9) was generally not detected, nor was the triene/tetraene ratio abnormal except for in two patients. There was no correlation between plasma linoleate and age, clinical severity score, or vitamin E status. Decreased linoleate did correlate with two indices of malabsorption, namely plasma carotene (r = 0.64) and fecal fat excretion (r = 0.76). Our data therefore indicate that the abnormality in linoleate is associated with (secondary to) malabsorption of dietary fat despite pancreatic enzyme replacement therapy and consumption of a regular diet. The frequency of this alteration was determined to be quite high in 40 patients with steatorrhea, 85% of whom showed values below the lower limit of normal for plasma linoleate. It was of interest to find markedly decreased levels of linoleate in adipose tissue, cardiac muscle, and lung and lesser reductions in liver and psoas muscle taken at autopsies. Tissue arachidonic acid percentage was normal, however, and 20:3 omega 9 was rarely present. Thus, the physiological significance of this common abnormality in CF patients with malabsorption remains to be determined.

Topics: Adipose Tissue; Adult; Arachidonic Acid; Arachidonic Acids; Child; Chromatography, Thin Layer; Cystic Fibrosis; Exocrine Pancreatic Insufficiency; Fatty Acids; Fatty Acids, Monounsaturated; Humans; Linoleic Acid; Linoleic Acids; Lipids; Malabsorption Syndromes; Oleic Acid; Oleic Acids; Palmitic Acid; Palmitic Acids; Vitamin E; Vitamin E Deficiency

A study was carried out in order to investigate whether the abnormal in vitro turnover of fatty acids in the phospholipids of the red blood cell membranes of cystic fibrosis patients is intrinsic to the membrane, or whether it is induced by extrinsic serum factors. Red blood cells of cystic fibrosis patients and healthy subjects were labeled in vitro with [14C]linoleic acid, bound to albumin. The labeled cells were reincubated in autologous and homologous serum. The radioactivity present in the serum lipids and in the major phospholipid fractions of the red cell membranes was measured. Conclusions of this study are: 1) not all of the cystic fibrosis patients examined individually show an abnormal in vitro turnover of the red cell fatty acids, although they all presented abnormal fatty acid patterns for the red blood cell phospholipids, the platelet phospholipids, and the plasma lipids. 2) The in vitro abnormal fatty acid turnover occurs only in the incubations where red cells of cystic fibrosis patients are involved (in homologous and autologous serum) and not where red cells of healthy subjects are incubated in serum of cystic fibrosis patients. Consequently, the abnormal turnover is intrinsic to the red cells and is not induced by extrinsic serum factors.

Topics: Adolescent; Adult; Blood Platelets; Cystic Fibrosis; Erythrocyte Membrane; Fatty Acids; Female; Humans; Linoleic Acid; Linoleic Acids; Male; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids

Possible relationships between zinc and essential fatty acid metabolism have been assessed using plasma samples obtained from 39 cystic fibrosis patients. The fatty acid composition of plasma phospholipids was analyzed by capillary gas liquid chromatography and zinc levels were measured by atomic absorption spectrometry. Computer analyses revealed positive correlations between zinc levels and (a) arachidonic acid (p less than 0.001), (b) the arachidonate/linoleate ratio (p less than 0.02), and (c) eicosatrienoic acid (n-6) (p less than 0.001). These observations suggest that conversion of linoleate to arachidonate may be modulated by zinc.

Topics: Adolescent; Arachidonic Acid; Arachidonic Acids; Child; Child, Preschool; Cystic Fibrosis; Fatty Acids, Essential; Humans; Linoleic Acid; Linoleic Acids; Zinc