Dataset Information

Fish Oil Derived Omega 3 Fatty Acids Suppress Adipose NLRP3 Inflammasome Signaling in Human Obesity.

ABSTRACT:

Context

The NRLP3 inflammasome is a multiprotein danger-sensing complex that serves as a critical link between obesity-related adipose inflammation and insulin resistance and has been shown in animal models to be inhibited by fish oil-derived long chain omega-3 polyunsaturated fatty acids (n-3 PUFA).

Objective

We conducted a clinical trial and in vitro experiments to test our hypothesis that n-3 PUFA suppress NLRP3 inflammasome in human obesity through downregulation of inflammasome gene expression in adipocytes and macrophages.

Design

Placebo-controlled clinical trial and in vitro coculture experiments with primary human adipocytes (from biopsy specimens) and human THP-1 monocyte-derived macrophages treated with eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA) vs vehicle control.

Setting

General community, research laboratory.

Patients and other participants

Obese (body mass index ≥ 30 kg/m²), nondiabetic males and females age 18 to 50. N = 25.

Interventions

Clinical trial: Eight-week treatment with 4 g Lovaza (EPA and DHA) or placebo. Cells culture: EPA and/or DHA at 100 µg/mL or vehicle control in culture medium.

Main outcome measures

Adipose tissue or adipocyte/macrophage mRNA expression of IL-1β and IL-18 and circulating IL-18 levels.

Results

Treatment of obese human subjects with fish oil supplements reduced expression of adipose inflammatory genes including inflammasome-associated IL-18 and IL-1β and circulating IL-18 levels. Both EPA and DHA reduced inflammasome gene expression in obese human adipose and human adipocyte and macrophages.

Conclusions

N-3 PUFA reduce NLRP3 inflammasome in human adipose through downregulation of gene expression in adipocytes and monocytes/macrophages and has potential as nutritional therapeutic agent in prevention of obesity-related inflammation.

SUBMITTER: Lee KR

PROVIDER: S-EPMC6371080 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Fish Oil Derived Omega 3 Fatty Acids Suppress Adipose NLRP3 Inflammasome Signaling in Human Obesity.

Lee Kailey Roberts KR Midgette Yasmeen Y Shah Rachana R

Journal of the Endocrine Society 20181224 3

<h4>Context</h4>The NRLP3 inflammasome is a multiprotein danger-sensing complex that serves as a critical link between obesity-related adipose inflammation and insulin resistance and has been shown in animal models to be inhibited by fish oil-derived long chain omega-3 polyunsaturated fatty acids (<i>n</i>-3 PUFA).<h4>Objective</h4>We conducted a clinical trial and <i>in vitro</i> experiments to test our hypothesis that <i>n</i>-3 PUFA suppress NLRP3 inflammasome in human obesity through downreg ...[more]

PMID: 30788452

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Project description:Background and Aims: Fish oil and krill oil are primary sources of Omega-3 polyunsaturated fatty acids (PUFAs), differing in their molecular forms and bioavailability. Understanding these differences can optimize their therapeutic use. This study aims to compare the bioavailability of Omega-3 PUFAs in fish oil and krill oil using a network meta-analysis approach. By evaluating various molecular forms and dosages, the study seeks to identify the most effective Omega-3 sources and dosing regimens to maximize health benefits. Methods: The study adhered to the explanation of the PRISMA network meta-analysis 2015 (registered PROSPERO ID: CRD42024532536). The risk of bias was evaluated using the PEDro scale. This network meta-analysis incorporated data from studies published between 2003 and 2023, sourced from five databases: ClinicalTrials.gov, PubMed, Cochrane CENTRAL, the International Clinical Trials Registry Platform-World Health Organization, and Embase. Statistical analysis was conducted using advanced models in R software to ensure a rigorous evaluation of bioavailability. Results: Out of 26 high-quality studies, findings reveal superior bioavailability of krill oil compared to fish oil. Specifically, fish oil above 3000 mg, in re-esterified triacylglycerol or ethyl ester formulations (100-2900 mg), and krill oil (100-1900 mg) significantly enhanced the Omega-3 index. At lower dosages (under 2000 mg), krill oil shows superior Omega-3 absorption compared to fish oil. Using fish oil ethyl ester at doses between 2000 and 2900 mg may be the most effective for reducing Tmax. However, this finding should be interpreted with caution due to high heterogeneity and limited statistical significance. The highest AUC values were observed in krill oil phospholipid/free fatty acid formulation. Emulsion forms of fish oil are more effective in increasing Cmax than other formulations. These results were supported by robust statistical evidence (Egger's test, p > 0.05), highlighting the effectiveness of specific formulations and doses in optimizing Omega-3 absorption. Conclusion: The research highlights the importance of understanding the bioavailability of Omega-3 PUFAs from fish oil and krill oil. The findings suggest that low-dose krill oil and fish oil emulsions (under 2000 mg) are effective and potentially safer alternatives to high-dose fish oil, potentially minimizing the risk of adverse effects.

Project description:ObjectiveOmega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), likely prevent cardiovascular disease, however their mechanisms remain unclear. Recently, the role of DNA damage in atherogenesis has been receiving considerable attention. Here, we investigated the effects of EPA and DHA on DNA damage in vascular endothelial cells to clarify their antiatherogenic mechanisms.Methods and resultsWe determined the effect of EPA and DHA on H2O2-induced DNA damage response in human aortic endothelial cells. Immunofluorescence staining showed that γ-H2AX foci formation, a prominent marker of DNA damage, was significantly reduced in the cells treated with EPA and DHA (by 47% and 48%, respectively). H2O2-induced activation of ATM, a major kinase orchestrating DNA damage response, was significantly reduced with EPA and DHA treatment (by 31% and 33%, respectively). These results indicated EPA and DHA attenuated DNA damage independently of the DNA damage response. Thus the effects of EPA and DHA on a source of DNA damage were examined. EPA and DHA significantly reduced intracellular reactive oxygen species under both basal condition and H2O2 stimulation. In addition, the mRNA levels of antioxidant molecules, such as heme oxygenase-1, thioredoxin reductase 1, ferritin light chain, ferritin heavy chain and manganese superoxide dismutase, were significantly increased with EPA and DHA. Silencing nuclear factor erythroid 2-related factor 2 (NRF2) remarkably abrogated the increases in mRNA levels of antioxidant molecules and the decrease in intracellular reactive oxygen species. Furthermore, EPA and DHA significantly reduced H2O2-induced senescence-associated β-galactosidase activity in the cells (by 31% and 22%, respectively), which was revoked by NRF2 silencing.ConclusionsOur results suggested that EPA and DHA attenuate oxidative stress-induced DNA damage in vascular endothelial cells through upregulation of NRF2-mediated antioxidant response. Therefore omega-3 fatty acids likely help prevent cardiovascular disease, at least in part, by their genome protective properties.

Project description:BackgroundPeroxisome proliferator-activated receptors (PPARalpha, PPARgamma, and PPARdelta) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARalpha agonists which lower lipid level, and glitazones as PPARgamma agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARalpha/gamma would be a logical approach. But synthetically developed PPARalpha/gamma dual agonists and glitazones are showing side effects such as weight gain and edema. Therefore, natural compounds and their close derivatives are focused as future drugs against metabolic diseases.Presentation of hypothesisDocosahexaenoic acid and eicosapentaenoic acid, which are the fatty acids abundant in fish oil, are traditionally used against metabolic diseases. These fatty acids act as PPAR agonists that transcript the genes involved in glucose and lipid homeostasis. Present hypothesis suggests that the derivatives of these fatty acids are stronger PPAR agonists than the parent compounds. X-ray structures of PPARs indicate that alpha or beta derivatives of fatty acids would fit into PPARalpha/gamma binding cavity. Therefore, the derivatives will exhibit stronger affinities and activities than the parent compounds.Testing of the hypothesisLigand binding assays and gene transactivation assays should be performed to test the hypothesis. Fluorescence-based methods are advantageous in binding assays, because they were found more suitable for fatty acid binding assays. In transactivation assays, care should be taken to remove contaminants from recombinant proteins.Implications of the hypothesisPresent hypothesis is framed on the basis of molecular structure of natural PPAR agonists. Small structural changes in the molecular structure of fatty acids have a great influence on activating different PPARs. Therefore, this hypothesis bridges the concept of natural PPAR agonists and the use of structural information in designing new drugs against diabetes and metabolic syndrome. The derivatives may also be used as anti-inflammatory and anticancer agents.

Dataset Information

Fish Oil Derived Omega 3 Fatty Acids Suppress Adipose NLRP3 Inflammasome Signaling in Human Obesity.

Context

Objective

Design

Setting

Patients and other participants

Interventions

Main outcome measures

Results

Conclusions

Publications

Fish Oil Derived Omega 3 Fatty Acids Suppress Adipose NLRP3 Inflammasome Signaling in Human Obesity.

Similar Datasets

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