Polyunsaturated Fatty Acids from Astrocytes Activates PPAR Gamma Signaling in Cancer Cells to Promote Brain Metastasis
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PROVIDER: PRJNA566243 | ENA |
REPOSITORIES: ENA
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Project description:Analysis of variation in subcutaneous adipose tissue gene expression in response to dietary intake of n-3 polyunsaturated fatty acids, as assessed in a cohot of individuals with metabolic syndrome. Outcomes from this study provide insight on molecular details of dietary effects on gene expression and metabolic health.
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Project description:Dietary polyunsaturated fatty acids (PUFA) act as potent natural hypolipidemics and are linked to many health benefits in humans and in animal models. Mice fed long-term a high fat diet, in which medium-chain alpha linoleic acid (ALA) was partially replaced by long-chain docosahexaenoic (DHA) and eicosapentaenoic (EPA) fatty acids, showed reduced accumulation of body fat and prevention of insulin resistance, besides increased mitochondrial beta-oxidation in white adipose tissue and decreased plasma lipids. ALA, EPA and DHA all belong to PUFA of n-3 series. The intestine is a gatekeeper organ for ingested lipids. To examine the potential contribution of the intestine in the beneficial effects of EPA and DHA, this study assessed gene expression changes using whole genome microarray analysis on small intestinal scrapings. The main biological process affected was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR and intestinal fatty acid oxidation measurements ([14C(U)]-palmitate) confirmed significant gene expression differences in a dose-dependent manner. Furthermore, no major changes in the expression of lipid metabolism genes were observed in colonic scrapings. In conclusion, we show that marine n-3 fatty acids regulate small intestinal gene expression patterns. Since this organ contributes significantly to whole organism energy use, this adaptation of the small intestine may contribute to the complex and observed beneficial physiological effects of these natural compounds under conditions that will normally lead to development of obesity and diabetes.
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Project description:In the present study, we investigated the consequences of n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic lipid metabolism in mice fed during three months with a diet presenting a high n-6/n-3 PUFA ratio to induce n-3 PUFA depletion. Microarray analyses were performed to identify the molecular targets involved in the development of hepatic steatosis associated with n-3 PUFA depletion. Male C57Bl/6J mice (9 weeks old) were housed in groups of four mice per cage at 22°C in a 12h light/dark cycle and given free access to diet and water. After an acclimatization period of 1 week, the mice were fed a control (CT) or an n-3 PUFA-depleted diet (DEF) for 3 months. At the end of the study period, mice (CT, n=6; DEF, n=7) were anesthetized after a 6h period of fasting. Some mice (CT: n=4 et DEF: n=7) were anesthetized without being starved. A fraction of the main liver lobe was fixed-frozen in isopentane and kept at -80°C for histological analysis. The excess tissue material was immediately clamped in liquid N2 and kept at -80°C. All mice experiments were approved by the local animal ethics committee, and the housing conditions were as specified by the Belgian Law of November 14, 1993 on the protection of laboratory animals (agreement n° LA 1230314).
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Project description:Very-long-chain polyunsaturated fatty acids (VLCPUFA; C24-38) that contain between 5-6 unsaturated double bonds are a unique class of PUFA that are primarily found in the retina, brain and testes. VLCPUFA appear to have important biological roles that cannot be fulfilled by the more common shorter-chain PUFA, but the lack of a suitable dietary source of VLCPUFA have limited research in this field. Typically, fish oils contain only a small amount of VLCPUFA (<1%, w/w), but we were able to produce a fish oil concentrate that contained over 40% by weight of n-3 VLCPUFA, with chain lengths between C24 and C28. A single-dose oral gavage of the VLCPUFA-oil in C57BL/6J mice resulted in a 9-fold increase in plasma levels of C24:5 n-3 by 2 hours. This was followed by a 70% increase in the retinal level of C24:5 n-3 after 8 hours from the gavage. Long-term (8-week) dietary supplementation with 1% or 5% (w/w) of VLCPUFA-oil in chow diet did not cause any adverse changes in the plasma chemistry profile or evidence of histologic injury to multiple tissues. It was found to alter the lipid composition of the liver, brain and eye in 11-month-old C57BL/6J mice. The VLCPUFA supplementation also caused favorable cardiometabolic changes by lowering plasma glucose, insulin, cholesterol and triglyceride levels. Furthermore, mice treated with the VLCPUFA oil had improved electroretinography response and visual performance after 15 consecutive days of oral gavage. Transcriptomic analysis of treated mice revealed significant alternation in genes involved in PPAR signaling pathways. Further in vitro studies demonstrated that the VLCPUFA-oil and chemically synthesized C24:5 n-3 are potent agonists for both PPAR-alpha and gamma. In conclusion, the multiple potential beneficial effects of fish-derived VLCPUFA-oil on eye health and cardiometabolic risk in mice support future efforts to develop VLCPUFA-oil into a novel therapy.
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Project description:Okra (Abelmoschus esculentus (L.) Moench) serves as a botanical resource extensively utilized in ethnomedicine. Prior investigations revealed that okra polysaccharide (OP) ameliorated hepatocellular lipotoxicity in vitro context. Nonetheless, the curative efficacy and the precise molecular mechanisms implicated in metabolic-associated fatty liver disease (MAFLD) warrant further elucidation. To address this gap, two murine models of MAFLD, namely obese Ob/Ob mice and high fat/cholesterol/fructose (HFCF) fed mice, were employed. The therapeutic implications of OP supplementation were assessed through quantification of lipid specific biomarkers and hepatic histopathological examination. Complementary transcriptomic, phosphoproteomic, and in vitro analyses were conducted to decipher the molecular underpinnings. In the Ob/Ob mouse model, OP substantively mitigated both circulating and hepatic lipid concentrations, concurrently ameliorating hepatic steatosis. In the context of HFCF-induced MAFLD, OP not only attenuated hepatic lipidic sequestration but also abrogated concomitant inflammation and fibrosis. Subsequent RNA-sequencing analyses on hepatic tissues derived from HFCF-diet mice delineated that OP modulated MAFLD-associated transcriptional signatures. A synergistic assessment of transcriptomics and phosphoproteomics disclosed a salient effect of OP on the Peroxisome Proliferator-Activated Receptor (PPAR) pathway, particularly manifested by the upregulation of PPAR-γ signaling. In murine hepatocytes, OP counteracted steatosis and inflammation via the activation of PPAR-γ signaling. The effects induced by OP were nullified upon administration of the PPAR-γ-specific antagonist GW9662. Collectively, our empirical evidence furnishes the inaugural demonstration that OP mitigates MAFLD pathology through the activation of PPAR-γ signaling, thereby presenting a novel therapeutic avenue for MAFLD intervention.
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