Docosahexaenoic acid-containing choline phospholipid modulates LPS-induced neuroinflammation in vivo and in microglia in vitro

BACKGROUND: Neuroinflammatory processes are considered a double-edged sword, having both protective and detrimental effects in the brain. Microglia, the brain's resident innate immune cells, are a key component of neuroinflammatory response. There is a growing interest in developing drugs to target microglia and control neuroinflammatory processes. In this regard, docosahexaenoic acid (DHA), the brain's n-3 polyunsaturated fatty acid, is a promising molecule to regulate pro-inflammatory microglia and cytokine production. Several works reported that the bioavailability of DHA to the brain is higher when DHA is acylated to phospholipid. In this work, we analyzed the anti-inflammatory activity of DHA-phospholipid, either acetylated at the sn-1 position (AceDoPC, a stable form thought to have superior access to the brain) or acylated with palmitic acid at the sn-1 position (PC-DHA) using a lipopolysaccharide (LPS)-induced neuroinflammation model both in vitro and in vivo. METHODS: In vivo, adult C57Bl6/J mice were injected intravenously (i.v.) with either AceDoPC or PC-DHA 24 h prior to LPS (i.p.). For in vitro studies, immortalized murine microglia cells BV-2 were co-incubated with DHA forms and LPS. AceDoPC and PC-DHA effect on brain or BV-2 PUFA content was assessed by gas chromatography. LPS-induced pro-inflammatory cytokines interleukin IL-1β, IL-6, and tumor necrosis factor (TNF) α production were measured by quantitative PCR (qPCR) or multiplex. IL-6 receptors and associated signaling pathway STAT3 were assessed by FACS analysis and western-blot in vitro. RESULTS: In vivo, a single injection of AceDoPC or PC-DHA decreased LPS-induced IL-6 production in the hippocampus of mice. This effect could be linked to their direct effect on microglia, as revealed in vitro. In addition, AceDoPC or PC-DHA reduced IL-6 receptor while only AceDoPC decreased IL-6-induced STAT3 phosphorylation. CONCLUSIONS: These results highlight the potency of administered DHA-acetylated to phospholipids-to rapidly regulate LPS-induced neuroinflammatory processes through their effect on microglia. In particular, both IL-6 production and signaling are targeted by AceDoPC in microglia.Metabolism in human of a structured phospholipid from marine origin and neural effec

Lipid dys-homeostasis contributes to APOE4-associated AD pathology

The association of the APOE4 (vs. APOE3) isoform with an increased risk of Alzheimer’s disease (AD) is unequivocal, but the underlying mechanisms remain incompletely elucidated. A prevailing hypothesis incriminates the impaired ability of APOE4 to clear neurotoxic amyloid-β peptides (Aβ) from the brain as the main mechanism linking the apolipoprotein isoform to disease etiology. The APOE protein mediates lipid transport both within the brain and from the brain to the periphery, suggesting that lipids may be potential co-factors in APOE4-associated physiopathology. The present study reveals several changes in the pathways of lipid homeostasis in the brains of mice expressing the human APOE4 vs. APOE3 isoform. Carriers of APOE4 had altered cholesterol turnover, an imbalance in the ratio of specific classes of phospholipids, lower levels of phosphatidylethanolamines bearing polyunsaturated fatty acids and an overall elevation in levels of monounsaturated fatty acids. These modifications in lipid homeostasis were related to increased production of Aβ peptides as well as augmented levels of tau and phosphorylated tau in primary neuronal cultures. This suite of APOE4-associated anomalies in lipid homeostasis and neurotoxic protein levels may be related to the accrued risk for AD in APOE4 carriers and provides novel insights into potential strategies for therapeutic intervention

Specific shifts in the endocannabinoid system in hibernating brown bears

In small hibernators, global downregulation of the endocannabinoid system (ECS), which is involved in modulating neuronal signaling, feeding behavior, energy metabolism, and circannual rhythms, has been reported to possibly drive physiological adaptation to the hibernating state. In hibernating brown bears (Ursus arctos), we hypothesized that beyond an overall suppression of the ECS, seasonal shift in endocannabinoids compounds could be linked to bear's peculiar features that include hibernation without arousal episodes and capacity to react to external disturbance. We explored circulating lipids in serum and the ECS in plasma and metabolically active tissues in free-ranging subadult Scandinavian brown bears when both active and hibernating. In winter bear serum, in addition to a 2-fold increase in total fatty acid concentration, we found significant changes in relative proportions of circulating fatty acids, such as a 2-fold increase in docosahexaenoic acid C22:6 n-3 and a decrease in arachidonic acid C20:4 n-6. In adipose and muscle tissues of hibernating bears, we found significant lower concentrations of 2-arachidonoylglycerol (2-AG), a major ligand of cannabinoid receptors 1 (CB1) and 2 (CB2). Lower mRNA level for genes encoding CB1 and CB2 were also found in winter muscle and adipose tissue, respectively. The observed reduction in ECS tone may promote fatty acid mobilization from body fat stores, and favor carbohydrate metabolism in skeletal muscle of hibernating bears. Additionally, high circulating level of the endocannabinoid-like compound N-oleoylethanolamide (OEA) in winter could favor lipolysis and fatty acid oxidation in peripheral tissues. We also speculated on a role of OEA in the conservation of an anorexigenic signal and in the maintenance of torpor during hibernation, while sustaining the capacity of bears to sense stimuli from the environment

Editorial for the Special Issue “Impacts of Transport Systems on Air Pollution and Human Health”

Transport systems (road, railway and aircraft traffic) are the main contributors to poor air quality in the major cities [...

Anti-inflammatory and anti-virus potential of poxytrins, especially protectin DX

International audiencePoxytrins (Pufa Oxygenated Trienes) are dihydroxy derivatives from polyunsaturated fatty acids (PUFA) with adjacent hydroxyl groups to a conjugated triene having the specific E,Z,E geometry. They are made by the double action of one lipoxygenase or the combined actions of two lipoxygenases, followed by reduction of the resulting hydroperoxides with glutathione peroxidase. Because of their E,Z,E conjugated triene, poxytrins may inhibit inflammation associated with cyclooxygenase (COX) activities, and reactive oxygen species (ROS) formation. In addition of inhibiting COX activities, at least one poxytrin, namely protectin DX (PDX) from docosahexaenoic acid (DHA), has also been reported as able to inhibit influenza virus replication by targeting its RNA metabolism

Synthesis and Biological Interest of Structured Docosahexaenoic Acid-Containing Triacylglycerols and Phospholipids

International audienceAbstract: In light of rapid progress in biochemistry and modern bioengineering, there is a great interest in understanding how modifying the structure of naturally occurring lipids can be used to improve their nutritional and health properties. Structured lipids (SLs) or custom-made lipids can supply functional fatty acids because of their specific positioning in the glycerol structure. Health benefits of n-3 fatty acids such as docosahexaenoic acid (DHA) have been widely reported. Little information is available on the potential for health benefits of the SLs molecules that are rich in DHA and have well defined structure.This review attempts to summarize our present state of knowledge of various approaches to produce structured DHA-containing triglycerides and phospholipids as well as their applications

Esterification of Docosahexaenoic Acid Enhances Its Transport to the Brain and Its Potential Therapeutic Use in Brain Diseases

Docosahexaenoic acid-containing lysophosphatidylcholine (DHA-LysoPC) is presented as the main transporter of DHA from blood plasma to the brain. This is related to the major facilitator superfamily domain-containing protein 2A (Mfsd2a) symporter expression in the blood–brain barrier that recognizes the various lyso-phospholipids that have choline in their polar head. In order to stabilize the DHA moiety at the sn-2 position of LysoPC, the sn-1 position was esterified by the shortest acetyl chain, creating the structural phospholipid 1-acetyl,2-docosahexaenoyl-glycerophosphocholine (AceDoPC). This small structure modification allows the maintaining of the preferential brain uptake of DHA over non-esterified DHA. Additional properties were found for AceDoPC, such as antioxidant properties, especially due to the aspirin-like acetyl moiety, as well as the capacity to generate acetylcholine in response to the phospholipase D cleavage of the polar head. Esterification of DHA within DHA-LysoPC or AceDoPC could elicit more potent neuroprotective effects against neurological diseases

Métabolisme et fonctions des acides gras oméga-3 à longue chaîne au niveau de l'adipocyte

Les acides gras polyinsaturés n-3 (AGPI n-3) d'origine marine, les acides eicosapentaénoïque (EPA) et docosahexaénoïque (DHA), exercent des effets bénéfiques potentiels sur la santé en particulier dans les maladies cardiovasculaires, l'obésité et le diabète de type 2. Le DHA protégerait notamment contre l'insuline-résistance et l'obésité chez les rongeurs et augmenterait la sensibilité à l'insuline chez l'Homme sain. Notre étude vise à déterminer dans un premier temps, chez la souris, les cinétiques d'incorporation du DHA dans les phospholipides de différents tissus ainsi que les effets d'une supplémentation en DHA sur les sécrétions d'adiponectine et de leptine plasmatiques, deux cytokines connues pour participer à la régulation de la sensibilité à l'insuline. Nous montrons une amélioration du profil d'adipokines sécrétées chez les souris ayant eu une alimentation enrichie en DHA. Cet effet s'accompagne d'une augmentation rapide de l'incorporation du DHA dans les phospholipides de tous les tissus analysés. Ces effets bénéfiques sont rapides puisqu'ils sont observés dès le 4ème jour de régime et durables puisqu'ils sont toujours observés 16 jours après l'arrêt de la supplémentation en DHA. Nous montrons également une augmentation de la sécrétion d'adiponectine chez des souris ayant été nourries avec une alimentation enrichie en EPA. ' Dans un second temps, nous avons étudié les effets de I'EPA et du DHA ainsi que de leurs dérivés oxygénés respectifs sur la sécrétion d'adiponectine par des adipocytes 3T3-L 1 en culture. Nous observons une augmentation de la sécrétion d'adiponectine après enrichissement des cellules avec ces AGPI n-3.N-3 polyunsaturated fatty acids (n-3 PUFA) of marine origin, eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids, potentially do beneficial health effects, mainly in cardiovascular diseases, obesity and type 2 diabetes. DHA protects against insulin resistance and obesity in rodents and increases insulin sensitivity in healthy humans. The first objective of our study was to determine the time course of DHA incorporation into phospholipids of different tissues in mice and the effects of DHA supplementation on plasma adiponectin and leptin secretions, two cytokines known to participate in the regulation of insuline sensitivity. We showed an improvement of the secreted adipokine profile in mice fed the DHA-rich diet. This effect was associated with a significant increase in DHA incorporation into phospholipids of all analyzed tissues. The beneficial effects on adipokines were fast, since they were observed as early as 4 days after the initiation of the DHA-rich diet, and long lasting as they were still observed 16 days after the arrest of DHA-rich diet feeding . We also showed an increased adiponectin secretion in mice fed an EPA-rich diet. We then studied the effects of EPA and DHA, and that of their oxygenated derivatives on adiponectin secretion in 3T3-L 1 adipocytes. We observed an increased adiponectin secretion after cell enrichment with these n-3 PUFA. Our results suggest that oxygenated metabolites could contribute to this effect. Regarding DHA, we showed a significant increase in adiponectin secretion after cell incubation with protectin DX (PDX). We also showed that only PDX, which has a E,Z,E-conjugated triene motif in his structure, increased adiponectins.VILLEURBANNE-DOC'INSA LYON (692662301) / SudocSudocFranceF

Bioavailability of lipids in fish and fish oils

International audienceThe health benefits of fish and fish lipid consumption have been proven and, amongst the active molecules, n–3 long-chain fatty acids (n–3 LC-PUFA, notably EPA and DHA) have been put forward. Currently, seafood is the primary dietary source of EPA and DHA, but specific dietary supplements are also being developed, including fish oil capsules and the design of specific molecular carriers. The aims of this chapter are to (1) summarize the lipid composition and specificity in fish and fish oils, (2) define their molecular and supramolecular carrier forms in different food products and supplements, (3) discuss their fate during digestion which partly determines their bioaccessibility, and (4) review their health or metabolic impact as related to the supplied form. Finally, further thoughts are provided to better address this topic from the formulation, food or supplement processing viewpoint. Reviews are provided of specific metabolic studies evaluating fish oil bioavailability