Dietary Supplementation With Eicosapentaenoic Acid Inhibits Plasma Cell Differentiation and Attenuates Lupus Autoimmunity.
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ABSTRACT:
SUBMITTER: Kobayashi A
PROVIDER: S-EPMC8240640 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Current therapies for treatment of myeloid leukemia do not eliminate leukemia stem cells (LSC), leading to disease relapse. In this study, we supplemented mice with eicosapentaenoic acid (EPA, C20:5), a polyunsaturated omega-3 fatty acid, at pharmacologic levels, to examine whether the endogenous metabolite, cyclopentenone prostaglandin delta-12 PGJ3 (?(12)-PGJ3), was effective in targeting LSCs in experimental leukemia. EPA supplementation for 8 weeks resulted in enhanced endogenous production of ?(12)-PGJ3 that was blocked by indomethacin, a cyclooxygenase (COX) inhibitor. Using a murine model of chronic myelogenous leukemia (CML) induced by bone marrow transplantation of BCR-ABL-expressing hematopoietic stem cells, mice supplemented with EPA showed a decrease in the LSC population, and reduced splenomegaly and leukocytosis, when compared with mice on an oleic acid diet. Supplementation of CML mice carrying the T315I mutation (in BCR-ABL) with EPA resulted in a similar effect. Indomethacin blocked the EPA effect and increased the severity of BCR-ABL-induced CML and decreased apoptosis. ?(12)-PGJ3 rescued indomethacin-treated BCR-ABL mice and decreased LSCs. Inhibition of hematopoietic-prostaglandin D synthase (H-PGDS) by HQL-79 in EPA-supplemented CML mice also blocked the effect of EPA. In addition, EPA supplementation was effective in a murine model of acute myeloid leukemia. EPA-supplemented mice exhibited a decrease in leukemia burden and a decrease in the LSC colony-forming unit (LSC-CFU). The decrease in LSCs was confirmed through serial transplantation assays in all disease models. The results support a chemopreventive role for EPA in myeloid leukemia, which is dependent on the ability to efficiently convert EPA to endogenous COX-derived prostanoids, including ?(12)-PGJ3.
| S-EPMC4596789 | biostudies-literature
Project description:Non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of obesity, is an emerging risk factor for hepatocellular carcinoma (HCC). Accumulating evidence has shown that chronic inflammation represents a plausible link between obesity and HCC and that the pro-inflammatory cytokine interleukin (IL)-6 contributes to the development of obesity-related HCC. In the present study, we aimed to examine the therapeutic potential of the omega-3 polyunsaturated fatty acid, eicosapentaenoic acid (EPA), which exerts anti-inflammatory effects. The results showed that the development of carcinogen-induced HCC was significantly less in mice fed a high-fat diet (HFD) supplemented with EPA than in those fed HFD only, suggesting that EPA attenuates the development of obesity-related HCC. Although EPA did not appear to affect obesity-linked inflammation, it suppressed the activation of the pro-tumorigenic IL-6 effector STAT3, contributing to the inhibition of tumor growth. These findings suggest a clinical implication of EPA as a treatment for obesity-related HCC.
| S-EPMC5862334 | biostudies-literature
Project description:Recently, we identified a novel mechanism of lipotoxicity in the kidney proximal tubular cells (PTECs); lipid overload stimulates macroautophagy/autophagy for the renovation of plasma and organelle membranes to maintain the integrity of the PTECs. However, this autophagic activation places a burden on the lysosomal system, leading to a downstream suppression of autophagy, which manifests as phospholipid accumulation and inadequate acidification in lysosomes. Here, we investigated whether pharmacological correction by eicosapentaenoic acid (EPA) supplementation could restore autophagic flux and alleviate renal lipotoxicity. EPA supplementation to high-fat diet (HFD)-fed mice reduced several hallmarks of lipotoxicity in the PTECs, such as phospholipid accumulation in the lysosome, mitochondrial dysfunction, inflammation, and fibrosis. In addition to improving the metabolic syndrome, EPA alleviated renal lipotoxicity via several mechanisms. EPA supplementation to HFD-fed mice or the isolated PTECs cultured in palmitic acid (PA) restored lysosomal function with significant improvements in the autophagic flux. The PA-induced redistribution of phospholipids from cellular membranes into lysosomes and the HFD-induced accumulation of SQSTM1/p62 (sequestosome 1), an autophagy substrate, during the temporal and genetic ablation of autophagy were significantly reduced by EPA, indicating that EPA attenuated the HFD-mediated increases in autophagy demand. Moreover, a fatty acid pulse-chase assay revealed that EPA promoted lipid droplet (LD) formation and transfer from LDs to the mitochondria for beta-oxidation. Noteworthy, the efficacy of EPA on lipotoxicity is autophagy-dependent and cell-intrinsic. In conclusion, EPA counteracts lipotoxicity in the proximal tubule by alleviating autophagic numbness, making it potentially suitable as a novel treatment for obesity-related kidney diseases.Abbreviations: 4-HNE: 4-hydroxy-2-nonenal; ACTB: actin beta; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; ATG: autophagy-related; ATP: adenosine triphosphate; BODIPY: boron-dipyrromethene; BSA: bovine serum albumin; cKO: conditional knockout; CML: N-carboxymethyllysine; COL1A1: collagen type I alpha 1 chain; COX: cytochrome c oxidase; CTRL: control; DGAT: diacylglycerol O-acyltransferase; EPA: eicosapentaenoic acid; FA: fatty acid; FFA: free fatty acid; GFP: green fluorescent protein; HFD: high-fat diet; iKO: inducible knockout; IRI: ischemia-reperfusion injury; LAMP1: lysosomal-associated membrane protein 1; LD: lipid droplet; LRP2: low density lipoprotein receptor-related protein 2; MAP1LC3: microtubule-associated protein 1 light chain 3; MTORC1: mechanistic target of rapamycin kinase complex 1; OA: oleic acid; PAS: periodic-acid Schiff; PPAR: peroxisome proliferator activated receptor; PPARGC1/PGC1: peroxisome proliferator activated receptor, gamma, coactivator 1; PTEC: proximal tubular epithelial cell; ROS: reactive oxygen species; RPS6: ribosomal protein S6; SDH: succinate dehydrogenase complex; SFC/MS/MS: supercritical fluid chromatography triple quadrupole mass spectrometry; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TG: triglyceride; TUNEL: terminal deoxynucleotidyl transferase dUTP nick end labeling.
| S-EPMC8354598 | biostudies-literature
Project description:BACKGROUND:Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have both shared and different cardiovascular effects, and commonly used fish oil supplements have considerably varied EPA/DHA ratios. AIMS:We compared the effects of fish oil supplements with different EPA/DHA ratios on lipoprotein metabolism. METHODS:In a double-blind, randomized cross-over study, normolipidemic adults (n = 30) consumed 12 g/day of EPA-rich (EPA/DHA: 2.3) or DHA-rich (EPA/DHA: 0.3) fish oil for 8-weeks, separated by an 8-week washout period. RESULTS:Both fish oil supplements similarly lowered plasma TG levels and TG-related NMR parameters versus baseline (p < 0.05). There were no changes in plasma cholesterol-related parameters due to either fish oil, although on-treatment levels for LDL particle number were slightly higher for DHA-rich oil compared with EPA-rich oil (p < 0.05). Both fish oil supplements similarly altered HDL subclass profile and proteome, and down regulated HDL proteins related to inflammation, with EPA-rich oil to a greater extent. Furthermore, EPA-rich oil increased apoM abundance versus DHA-rich oil (p < 0.05). CONCLUSIONS:Overall, fish oil supplements with varied EPA/DHA ratios had similar effects on total lipids/lipoproteins, but differences were observed in lipoprotein subfraction composition and distribution, which could impact on the use of EPA versus DHA for improving cardiovascular health.
| S-EPMC7146314 | biostudies-literature
Project description:Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44.
| S-EPMC5919878 | biostudies-other
Project description:We investigated the effects of purified eicosapentaenoic acid (EPA) on vascular endothelial function and free fatty acid composition in Japanese hyperlipidemic subjects. In subjects with hyperlipidemia (total cholesterol ?220?mg/dL and/or triglycerides ?150?mg/dL), lipid profile and forearm blood flow (FBF) during reactive hyperemia were determined before and 3 months after supplementation with 1800?mg/day EPA. Peak FBF during reactive hyperemia was lower in the hyperlipidemic group than the normolipidemic group. EPA supplementation did not change serum levels of total, HDL, or LDL cholesterol, apolipoproteins, remnant-like particle (RLP) cholesterol, RLP triglycerides, or malondialdehyde-modified LDL cholesterol. EPA supplementation did not change total free fatty acid levels in serum, but changed the fatty acid composition, with increased EPA and decreased linoleic acid, ?-linolenic acid, and dihomo-?-linolenic acid. EPA supplementation recovered peak FBF after 3 months. Peak FBF recovery was correlated positively with EPA and EPA/arachidonic acid levels and correlated inversely with dihomo-?-linolenic acid. EPA supplementation restores endothelium-dependent vasodilatation in hyperlipidemic patients despite having no effect on serum cholesterol and triglyceride patterns. These results suggest that EPA supplementation may improve vascular function at least partly via changes in fatty acid composition.
| S-EPMC3541561 | biostudies-literature
Project description:Th17 activity has been implicated in systemic lupus erythematosus (SLE), which is a systemic autoimmune disease with a typical clinical manifestation of lupus nephritis (LN). Retinoic acid receptor-related orphan receptor gamma t (RORγt) has been shown to be important for Th17 differentiation. In this study, we evaluated the inhibition of RORγt activity by 3β-acetyloxy-oleanolic acid (AOA), a small molecule isolated from the root of Symplocos laurina, a traditional herb belonging to South China. We demonstrated that AOA can inhibit RORγt activity and prevent SLE pathogenesis in a pristane-induced LN model. The results showed that AOA decreased RORγt transcription activity in a reporter assay and prevented Th17 differentiation in vitro. In vivo studies showed that AOA treatment decreased serum anti-dsDNA antibody and alleviated renal pathologic damage as well as antibody complex accumulation in the pristane-induced LN model. These results demonstrated that AOA can improve the clinical manifestation of LN, indicating potential application in SLE therapy.
| S-EPMC6556267 | biostudies-literature
Project description:Repeated short-term intranasal instillation of lupus-prone mice with crystalline silica (cSiO2) induces inflammatory gene expression and ectopic lymphoid neogenesis in the lung, leading to early onset of systemic autoimmunity and rapid progression to glomerulonephritis. These responses are suppressed by dietary supplementation with the ω-3 polyunsaturated fatty acid docosahexaenoic acid (DHA). Here, we tested the hypothesis that dietary DHA supplementation suppresses cSiO2-induced inflammatory proteins in bronchoalveolar alveolar lavage fluid (BALF) and plasma of lupus-prone mice. Archived tissue fluid samples were used from a prior investigation in which 6 wk-old lupus-prone female NZBWF1 mice were fed isocaloric diets containing 0 or 10 g/kg DHA for 2 wks and then intranasally instilled with 1 mg cSiO2 or vehicle once weekly for 4 wks. Cohorts were terminated at 1, 5, 9 or 13 wk post-instillation (PI). BALF and plasma from each cohort were analyzed by high density multiplex array profiling of 200 inflammatory proteins. cSiO2 time-dependently induced increases in the BALF protein signatures that were highly reflective of unresolved lung inflammation, although responses in the plasma were much less robust. Induced proteins in BALF included chemokines (e.g., MIP-2, MCP-5), enzymes (e.g., MMP-10, granzyme B), adhesion molecules (e.g., sE-selectin, sVCAM-1), co-stimulatory molecules (e.g., sCD40L, sCD48), TNF superfamily proteins (e.g., sTNFRI, sBAFF-R), growth factors (e.g., IGF-1, IGFBP-3), and signal transduction proteins (e.g., MFG-E8, FcgRIIB), many of which were blocked or delayed by DHA supplementation. The BALF inflammatory proteome correlated positively with prior measurements of gene expression, pulmonary ectopic lymphoid tissue neogenesis, and induction of autoantibodies in the lungs of the control and treatment groups. Ingenuity Pathway Analysis (IPA) revealed that IL-1β, TNF-α, and IL-6 were among the top upstream regulators of the cSiO2-induced protein response. Furthermore, DHA's effects were associated with downregulation of cSiO2-induced pathways involving i) inhibition of ARE-mediated mRNA decay, ii) bacterial and viral pattern recognition receptor activation, or iii) TREM1, STAT3, NF-κB, and VEGF signaling and with upregulation of PPAR, LXR/RXR and PPARα/RXRα signaling. Altogether, these preclinical findings further support the contention that dietary DHA supplementation could be applicable as an intervention against inflammation-driven autoimmune triggering by cSiO2 or potentially other environmental agents.
| S-EPMC8813772 | biostudies-literature
Project description:The objectives of this study were as follows: 1) to establish whether feeding a source of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to ewes during late gestation changes the fatty acid profile of colostrum, milk, ewe adipose tissue, and plasma and subsequently lamb plasma and red blood cells (RBC), and 2) to investigate the effects of EPA and DHA on mRNA expression in ewe adipose tissue. Eighty-four gestating ewes (28 pens, three per pen) were blocked by lambing day and assigned to a diet with an addition of fat at 0.39% of the DM during the last 50 d of gestation using Ca salts of a palm fatty acid distillate (PFAD) high in palmitic and oleic acids or EPA + DHA. Blood samples were taken from ewes on days 20, 1 (parturition), and 30 and from lambs on days 1 and 30 for plasma fatty acid analysis. Fatty analysis of lamb RBC was performed on day 1. Colostrum samples were taken at lambing and milk samples on day 30 for fatty acid analysis. Subcutaneous adipose tissue biopsies were taken from one ewe per pen on day 20 for fatty acid analysis and gene expression analysis of 27 genes. Treatment × day interactions (P < 0.10) were observed for several isomers of C18:1, with concentrations that were greater in plasma of EPA + DHA ewes on day 20, but were not different on day 1 or 30. Plasma concentrations of EPA tended to be greater (P = 0.07), whereas DHA was greater (P < 0.001) in EPA + DHA ewes compared with PFAD ewes. There was no difference in EPA or DHA in adipose tissue with EPA + DHA vs. PFAD supplementation (P > 0.10). Concentrations of fatty acids with 6 to 10 carbons were significantly increased (P < 0.05) in colostrum and milk of EPA + DHA ewes. There was a treatment × day interaction with EPA + DHA ewes yielding greater EPA (P = 0.03) and DHA (P = 0.04) concentrations than PFAD in colostrum, but not in milk. Treatment × day interactions (P < 0.05) were observed for several C18:1 isomers with concentrations that were greater in EPA + DHA ewe colostrum, but were not different between treatments in milk. In lamb plasma and RBC, EPA and DHA were not different between treatments (P > 0.10). The expression of fatty acid synthase and leptin was significantly increased (P < 0.05), whereas the expression of diacylglycerol acyltransferase 2 tended to be increased (P = 0.08) by supplementation of EPA + DHA vs. PFAD. These results suggest that supplementation with EPA and DHA to ewes during late gestation alters the fatty acid profile of plasma, colostrum, and milk and may increase lipogenesis.
| S-EPMC6093578 | biostudies-literature
Project description:PurposeTo evaluate the associations between intakes of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and the intermediate and advanced stages of age-related macular degeneration (AMD).DesignProspective cohort study.ParticipantsWe followed 75 889 women from the Nurses' Health Study and 38 961 men from the Health Professionals Follow-Up Study who were at least 50 years old, from 1984 to 2012 and 1986 to 2010, respectively. Cohort participants are mostly white (≥95%).MethodsWe assessed dietary intake by a validated food frequency questionnaire (FFQ) at baseline and every 4 years. We calculated cumulative average intakes of EPA and DHA from FFQs and also computed predicted erythrocyte and plasma scores directly from food intake using regression models. Cox proportional hazards models were used to compute the associations with AMD outcomes.Main outcome measuresWe confirmed 1589 incident intermediate and 1356 advanced AMD cases (primarily neovascular AMD) with a visual acuity of 20/30 or worse, owing primarily to AMD, by medical record review.ResultsFor intermediate AMD, the pooled hazard ratio (HR) between the 2 cohorts for DHA comparing the extreme quintiles of intake was 0.78 (95% confidence interval [CI], 0.66-0.92; P trend, 0.008) and for EPA + DHA was 0.83 (95% CI, 0.71-0.98; P trend, 0.03). The pooled HR for fatty fish, comparing ≥5 servings per week to almost never, was 0.61 (95% CI, 0.46-0.81; P trend, <0.001). For advanced AMD, the pooled HR for DHA was 1.01 (95% CI, 0.84-1.21; P trend, 0.75) and for fatty fish was 0.80 (95% CI, 0.59-1.08; P trend, 0.11). Secondary analyses using predicted erythrocyte and plasma scores of EPA and DHA yielded slightly stronger inverse associations for intermediate AMD and similar results for advanced AMD.ConclusionsHigher intakes of EPA and DHA may prevent or delay the occurrence of visually significant intermediate AMD. However, the totality of current evidence for EPA and DHA and advanced AMD is discordant, though there was no association with advanced AMD in the present study.
| S-EPMC5401792 | biostudies-literature