Lowering dietary n-6 polyunsaturated fatty acids

Alashmali, Shoug; Hopperton, Kathryn E.; Bazinet, Richard P.

doi:10.1097/mol.0000000000000255

Cited by 20 publications

(10 citation statements)

References 69 publications

(99 reference statements)

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“…However, these pro-inflammatory markers were not reduced by lowering dietary n-6 PUFA as previously hypothesized. A recent review shows that in studies reporting an effect on the brain n-6 PUFA, LA accounted for on average 30% difference of dietary fatty acids between n-6 PUFA deprived and adequate diets [36]; the difference in LA levels between both diets in a study similar to what we report here was ~ 20% [13], which may not be big enough to show major changes in inflammatory markers. Another possible reason for the minor changes in pro-inflammatory markers over time between diet groups is that the diet exposure (∼ 9 weeks) is shorter compared to those of previous studies [26], which were about 15 weeks of intervention.…”

Section: Discussionsupporting

confidence: 67%

The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

Alashmali

Lin

Trépanier

et al. 2019

J Neuroinflammation

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BackgroundNeuroinflammation is thought to contribute to psychiatric and neurological disorders such as major depression and Alzheimer’s disease (AD). N-6 polyunsaturated fatty acids (PUFA) and molecules derived from them, including linoleic acid- and arachidonic acid-derived lipid mediators, are known to have pro-inflammatory properties in the periphery; however, this has yet to be tested in the brain. Lowering the consumption of n-6 PUFA is associated with a decreased risk of depression and AD in human observational studies. The purpose of this study was to investigate the inflammation-modulating effects of lowering dietary n-6 PUFA in the mouse hippocampus.MethodsC57BL/6 male mice were fed either an n-6 PUFA deprived (2% of total fatty acids) or an n-6 PUFA adequate (23% of total fatty acids) diet from weaning to 12 weeks of age. Animals then underwent intracerebroventricular surgery, in which lipopolysaccharide (LPS) was injected into the left lateral ventricle of the brain. Hippocampi were collected at baseline and following LPS administration (1, 3, 7, and 14 days). A microarray (n = 3 per group) was used to identify candidate genes and results were validated by real-time PCR in a separate cohort of animals (n = 5–8 per group).ResultsMice administered with LPS had significantly increased Gene Ontology categories associated with inflammation and immune responses. These effects were independent of changes in gene expression in any diet group. Results were validated for the effect of LPS treatment on astrocyte, cytokine, and chemokine markers, as well as some results of the diets on Ifrd2 and Mfsd2a expression.ConclusionsLPS administration increases pro-inflammatory and lipid-metabolizing gene expression in the mouse hippocampus. An n-6 PUFA deprived diet modulated inflammatory gene expression by both increasing and decreasing inflammatory gene expression, without impairing the resolution of neuroinflammation following LPS administration.

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Section: Discussionsupporting

confidence: 67%

The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

Alashmali

Lin

Trépanier

et al. 2019

J Neuroinflammation

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“…This could be overcome by using positron emitting tomography to image fatty acid incorporation into the brain, as a way to quantify the amount lost due to metabolism (into oxylipins and other signaling molecules) [48, 49]. The changes in brain oxylipins suggest that dietary LA lowering could be used to target disturbed LA, AA or EPA metabolism in brain disorders [9, 49–51].…”

Section: Discussionmentioning

confidence: 99%

Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid

Taha

Hennebelle

Yang

et al. 2018

Prostaglandins, Leukotrienes and Essential Fatty Acids

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Linoleic acid (LA, 18:2n-6) is the most abundant polyunsaturated fatty acid in the North American diet and is a precursor to circulating bioactive fatty acid metabolites implicated in brain disorders. This exploratory study tested the effects of increasing dietary LA on plasma and cerebral cortex metabolites derived from LA, it’s elongation-desaturation products dihomo-gamma linolenic (DGLA, 20:3n-6) acid and arachidonic acid (AA, 20:4n-6), as well as omega-3 alpha-linolenic (α-LNA, 18:3n-3), eicosapentaenoic (EPA, 20:5n-3) and docosahexaenoic acid (DHA, 22:6n-3). Plasma and cortex were obtained from rats fed a 0.4%, 5.2% or 10.5% energy LA diet for 15 weeks and subjected to liquid chromatography tandem mass spectrometry analysis. Total oxylipin concentrations, representing the esterified and unesterified pool, and unesterified oxylipins derived from LA and AA were significantly increased and EPA metabolites decreased in plasma at 5.2% or 10.5% energy LA compared to 0.4% energy LA. Unesterified plasma DHA metabolites also decreased at 10.5% energy LA. Total oxylipins did not significantly change in cortex, whereas unesterified LA and AA metabolites increased and unesterified EPA metabolites decreased at 5.2 or 10.5% LA. DGLA and α-LNA metabolites did not significantly change in plasma or cortex. Dietary LA lowering represents a feasible approach for targeting plasma and brain LA, AA, EPA or DHA-derived metabolite concentrations.

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“…For example, LA is a polyunsaturated n‐6 essential fatty acid that serves as a precursor to the longer‐chain n‐6 AA 25. Increased concentrations of LA lead to higher inflammatory marker concentrations such as interleukin‐8 and elevated oxidative stress 26.…”

Section: Discussionmentioning

confidence: 99%

Novel Phospholipid Signature of Depressive Symptoms in Patients With Coronary Artery Disease

Chan

Suridjan

Mohammad

et al. 2018

JAHA

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BackgroundDepression in patients with coronary artery disease (CAD) is associated with increased cardiovascular morbidity. Given the proinflammatory actions of phospholipids, aberrant phospholipid metabolism may be an etiological mechanism linking CAD and depression. Our primary objective was to identify a phospholipid biomarker panel that characterizes CAD patients with significant depressive symptoms from those without.Methods and ResultsWe performed a targeted lipidomic analysis on CAD patients with significant depressive symptoms (n=37, Center for Epidemiologic Studies Depression score ≥16) and those without (n=49). Phospholipid species were selected using partial least‐square discriminant analysis, and the ability of the resulting model to discriminate between groups was evaluated using receiver operator characteristic curves. Biosignature scores were calculated from this model, and analyses of covariance were performed to compare intergroup differences in biosignature scores, with adjustment for clinical differences between patients. Those with significant depressive symptoms had lower cardiopulmonary fitness, more prevalent history of depression, and a greater number of vascular risk factors. A model of 10 phospholipid species had an area under the curve value of 0.84 (95% confidence interval 0.72‐0.95), sensitivity of 0.73, and specificity of 0.71. This model passed permutation testing (n=1000, P<0.001). Biosignature scores were higher in those with significant depressive symptoms after adjustment for potential confounders (F[1.86]=14.39, P<0.0005).ConclusionsThe present findings support the role of proinflammatory phospholipid species in the presence of depression in CAD patients from the CAROTID trial (Coronary Artery Disease Randomized Omega‐3 Trial in Depression). Future investigations should aim to replicate findings in larger data sets and clarify possible pathophysiological mechanisms.Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT00981383.

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Lowering dietary n-6 polyunsaturated fatty acids

Abstract: Lowering dietary n-6 PUFA, in animal models, can alter the levels and metabolism of ARA and DHA in the brain, but it remains to be determined whether these changes are clinically meaningful.

Cited by 20 publications

References 69 publications

The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

The effects of n-6 polyunsaturated fatty acid deprivation on the inflammatory gene response to lipopolysaccharide in the mouse hippocampus

Regulation of rat plasma and cerebral cortex oxylipin concentrations with increasing levels of dietary linoleic acid

Novel Phospholipid Signature of Depressive Symptoms in Patients With Coronary Artery Disease

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