The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Michelangelo Foti - One of the best experts on this subject based on the ideXlab platform.
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Unsaturated Fatty Acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor pten
Journal of Hepatology, 2009Co-Authors: Manlio Vinciguerra, Fabio Carrozzino, Marion Peyrou, S Carlone, Roberto Montesano, Roberto Benelli, Michelangelo FotiAbstract:BACKGROUND/AIMS: The impact of dietary Fatty Acids on the development of cancers is highly controversial. We recently demonstrated that Unsaturated Fatty Acids trigger the downregulation of the tumor suppressor PTEN through an mTOR/NF-kappaB-dependent mechanism in hepatocytes. In this study, we investigated whether Unsaturated Fatty Acids promote hepatoma progression by downregulating PTEN expression. METHODS: The effects of Fatty Acids and PTEN-specific siRNAs on proliferation, invasiveness and gene expression were assessed using HepG2 hepatoma cells. The tumor promoting activity of Unsaturated Fatty Acids was evaluated in vivo using HepG2 xenografts in nude mice. RESULTS: Incubation of HepG2 cells with Unsaturated Fatty Acids, or PTEN-specific siRNAs, increased cell proliferation, cell migration and invasiveness, and altered the expression of genes involved in inflammation, epithelial-to-mesenchymal transition and carcinogenesis. These effects were dependent on PTEN expression levels and were prevented by mTOR and NF-kappaB inhibitors. Consistent with these data, the development and size of subcutaneous HepG2-derived tumors in nude mice xenografts were dramatically increased when mice were fed with an oleic acid-enriched diet, even in the absence of weight gain. CONCLUSIONS: These data demonstrate that dietary Unsaturated Fatty Acids promote hepatoma progression by reducing the expression of the tumor suppressor PTEN.
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Unsaturated Fatty Acids inhibit the expression of tumor suppressor phosphatase and tensin homolog pten via microrna 21 up regulation in hepatocytes
Hepatology, 2009Co-Authors: Manlio Vinciguerra, Antonino Sgroi, Christelle Veyratdurebex, Laura Rubbiabrandt, L Buhler, Michelangelo FotiAbstract:UNLABELLED: Phosphatase and tensin homolog (PTEN) is a regulator of phosphoinositide 3-kinase signaling and an important tumor suppressor mutated/deleted in human cancers. PTEN deletion in the liver leads to insulin resistance, steatosis, inflammation, and cancer. We recently demonstrated that Unsaturated Fatty Acids trigger steatosis by down-regulating PTEN expression in hepatocytes via activation of a mammalian target of rapamycin (mTOR)/nuclear factor kappa B (NF-kappaB) complex, but the molecular mechanisms implicated in this process are still unknown. Here, we investigated potential genetic and epigenetic mechanisms activated by Fatty Acids leading to PTEN down-regulation. Our results indicate that Unsaturated Fatty Acids down-regulate PTEN messenger RNA expression in hepatocytes through mechanisms unrelated to methylation of the PTEN promoter, histone deacetylase activities, or repression of the PTEN promoter activity. In contrast, Unsaturated Fatty Acids up-regulate the expression of microRNA-21, which binds to PTEN messenger RNA 3'-untranslated region and induces its degradation. The promoter activity of microRNA-21 was increased by mTOR/NF-kappaB activation. Consistent with these data, microRNA-21 expression was increased in the livers of rats fed high-fat diets and in human liver biopsies of obese patients having diminished PTEN expression and steatosis. CONCLUSION: Unsaturated Fatty Acids inhibit PTEN expression in hepatocytes by up-regulating microRNA-21 synthesis via an mTOR/NF-kappaB-dependent mechanism. Aberrant up-regulation of microRNA-21 expression by excessive circulating levels of Fatty Acids exemplify a novel regulatory mechanism by which Fatty Acids affect PTEN expression and trigger liver disorders.
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pten down regulation by Unsaturated Fatty Acids triggers hepatic steatosis via an nf κbp65 mtor dependent mechanism
Gastroenterology, 2008Co-Authors: Manlio Vinciguerra, Christelle Veyratdurebex, Laura Rubbiabrandt, Moulay Ahmed Moukil, Francoise Rohnerjeanrenaud, Michelangelo FotiAbstract:Background & Aims: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor and a regulator of insulin sensitivity in peripheral tissues. In the liver, PTEN deletion increases insulin sensitivity, but induces steatosis, steatohepatitis, and hepatocellular carcinoma. Here, we investigated the pathophysiologic mechanisms regulating PTEN expression in the liver and the development of steatosis. Methods: PTEN expression was evaluated in the liver of rats and human beings having metabolic syndrome. Signaling pathways regulating PTEN expression and lipid accumulation in hepatocytes were examined in vitro. Results: PTEN expression is down-regulated in the liver of rats having steatosis and high plasma levels of Fatty Acids, as well as in steatotic human livers. Unsaturated Fatty Acids inhibited PTEN expression in HepG2 cells via activation of a signaling complex formed by the mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB). Down-regulation of PTEN expression induced steatosis by affecting import, esterification, and extracellular release of Fatty Acids. Conclusions: Hepatic steatosis can be mediated by alterations of PTEN expression in hepatocytes exposed to high levels of Unsaturated Fatty Acids. Furthermore, our data revealed interaction between mTOR and NF-κB, suggesting cross-talk between these 2 pathways.
Manlio Vinciguerra - One of the best experts on this subject based on the ideXlab platform.
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Unsaturated Fatty Acids promote hepatoma proliferation and progression through downregulation of the tumor suppressor pten
Journal of Hepatology, 2009Co-Authors: Manlio Vinciguerra, Fabio Carrozzino, Marion Peyrou, S Carlone, Roberto Montesano, Roberto Benelli, Michelangelo FotiAbstract:BACKGROUND/AIMS: The impact of dietary Fatty Acids on the development of cancers is highly controversial. We recently demonstrated that Unsaturated Fatty Acids trigger the downregulation of the tumor suppressor PTEN through an mTOR/NF-kappaB-dependent mechanism in hepatocytes. In this study, we investigated whether Unsaturated Fatty Acids promote hepatoma progression by downregulating PTEN expression. METHODS: The effects of Fatty Acids and PTEN-specific siRNAs on proliferation, invasiveness and gene expression were assessed using HepG2 hepatoma cells. The tumor promoting activity of Unsaturated Fatty Acids was evaluated in vivo using HepG2 xenografts in nude mice. RESULTS: Incubation of HepG2 cells with Unsaturated Fatty Acids, or PTEN-specific siRNAs, increased cell proliferation, cell migration and invasiveness, and altered the expression of genes involved in inflammation, epithelial-to-mesenchymal transition and carcinogenesis. These effects were dependent on PTEN expression levels and were prevented by mTOR and NF-kappaB inhibitors. Consistent with these data, the development and size of subcutaneous HepG2-derived tumors in nude mice xenografts were dramatically increased when mice were fed with an oleic acid-enriched diet, even in the absence of weight gain. CONCLUSIONS: These data demonstrate that dietary Unsaturated Fatty Acids promote hepatoma progression by reducing the expression of the tumor suppressor PTEN.
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Unsaturated Fatty Acids inhibit the expression of tumor suppressor phosphatase and tensin homolog pten via microrna 21 up regulation in hepatocytes
Hepatology, 2009Co-Authors: Manlio Vinciguerra, Antonino Sgroi, Christelle Veyratdurebex, Laura Rubbiabrandt, L Buhler, Michelangelo FotiAbstract:UNLABELLED: Phosphatase and tensin homolog (PTEN) is a regulator of phosphoinositide 3-kinase signaling and an important tumor suppressor mutated/deleted in human cancers. PTEN deletion in the liver leads to insulin resistance, steatosis, inflammation, and cancer. We recently demonstrated that Unsaturated Fatty Acids trigger steatosis by down-regulating PTEN expression in hepatocytes via activation of a mammalian target of rapamycin (mTOR)/nuclear factor kappa B (NF-kappaB) complex, but the molecular mechanisms implicated in this process are still unknown. Here, we investigated potential genetic and epigenetic mechanisms activated by Fatty Acids leading to PTEN down-regulation. Our results indicate that Unsaturated Fatty Acids down-regulate PTEN messenger RNA expression in hepatocytes through mechanisms unrelated to methylation of the PTEN promoter, histone deacetylase activities, or repression of the PTEN promoter activity. In contrast, Unsaturated Fatty Acids up-regulate the expression of microRNA-21, which binds to PTEN messenger RNA 3'-untranslated region and induces its degradation. The promoter activity of microRNA-21 was increased by mTOR/NF-kappaB activation. Consistent with these data, microRNA-21 expression was increased in the livers of rats fed high-fat diets and in human liver biopsies of obese patients having diminished PTEN expression and steatosis. CONCLUSION: Unsaturated Fatty Acids inhibit PTEN expression in hepatocytes by up-regulating microRNA-21 synthesis via an mTOR/NF-kappaB-dependent mechanism. Aberrant up-regulation of microRNA-21 expression by excessive circulating levels of Fatty Acids exemplify a novel regulatory mechanism by which Fatty Acids affect PTEN expression and trigger liver disorders.
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pten down regulation by Unsaturated Fatty Acids triggers hepatic steatosis via an nf κbp65 mtor dependent mechanism
Gastroenterology, 2008Co-Authors: Manlio Vinciguerra, Christelle Veyratdurebex, Laura Rubbiabrandt, Moulay Ahmed Moukil, Francoise Rohnerjeanrenaud, Michelangelo FotiAbstract:Background & Aims: Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is a tumor suppressor and a regulator of insulin sensitivity in peripheral tissues. In the liver, PTEN deletion increases insulin sensitivity, but induces steatosis, steatohepatitis, and hepatocellular carcinoma. Here, we investigated the pathophysiologic mechanisms regulating PTEN expression in the liver and the development of steatosis. Methods: PTEN expression was evaluated in the liver of rats and human beings having metabolic syndrome. Signaling pathways regulating PTEN expression and lipid accumulation in hepatocytes were examined in vitro. Results: PTEN expression is down-regulated in the liver of rats having steatosis and high plasma levels of Fatty Acids, as well as in steatotic human livers. Unsaturated Fatty Acids inhibited PTEN expression in HepG2 cells via activation of a signaling complex formed by the mammalian target of rapamycin (mTOR) and nuclear factor-κB (NF-κB). Down-regulation of PTEN expression induced steatosis by affecting import, esterification, and extracellular release of Fatty Acids. Conclusions: Hepatic steatosis can be mediated by alterations of PTEN expression in hepatocytes exposed to high levels of Unsaturated Fatty Acids. Furthermore, our data revealed interaction between mTOR and NF-κB, suggesting cross-talk between these 2 pathways.
Anne Brunet - One of the best experts on this subject based on the ideXlab platform.
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mono Unsaturated Fatty Acids link h3k4me3 modifiers to c elegans lifespan
Nature, 2017Co-Authors: Elizabeth A Schroeder, Katja Hebestreit, William B. Mair, Carlos G Silvagarcia, Anne BrunetAbstract:Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. However, the mechanism by which H3K4me3 modifiers affect longevity, and whether this mechanism involves metabolic changes, remain unclear. Here we show that a deficiency in H3K4me3 methyltransferase, which extends lifespan, promotes fat accumulation in worms with a specific enrichment of mono-Unsaturated Fatty Acids (MUFAs). This fat metabolism switch in H3K4me3 methyltransferase-deficient worms is mediated at least in part by the downregulation of germline targets, including S6 kinase, and by the activation of an intestinal transcriptional network that upregulates delta-9 Fatty acid desaturases. Notably, the accumulation of MUFAs is necessary for the lifespan extension of H3K4me3 methyltransferase-deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals. A deficiency in H3K4me3 methyltransferase causes accumulation of mono-Unsaturated Fatty Acids, which is important for lifespan extension in C. elegans and could be relevant in mammals. The lifespan of a worm is extended by H3K4me3 methyltransferase deficiency, but how and why remains unclear. Here it is shown that the loss of H3K4me3 in the germline affects fat metabolism in the worm intestine, resulting in the accumulation of mono-Unsaturated Fatty Acids (MUFAs), but not poly-Unsaturated Fatty Acids (PUFAs). The fat switch appears to be mediated in part by the downregulation of specific targets in the germline, including S6K, and the activation of a transcriptional network in the intestine leading to the upregulation of conserved delta-9 Fatty acid desaturases. MUFA accumulation is necessary for the increased longevity caused by H3K4me3-methyltransferase deficiency, and the authors found that dietary MUFAs, but not PUFAs, were sufficient to extend worm lifespan. Whether dietary or endogenous MUFAs could extend lifespan and healthspan in other species remains to be seen.
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Mono-Unsaturated Fatty Acids link H3K4me3 modifiers to C. elegans lifespan
Nature, 2017Co-Authors: Shuo Han, Carlos G. Silva-garcía, Katja Hebestreit, William B. Mair, Elizabeth A Schroeder, Anne BrunetAbstract:Chromatin and metabolic states both influence lifespan, but how they interact in lifespan regulation is largely unknown. The COMPASS chromatin complex, which trimethylates lysine 4 on histone H3 (H3K4me3), regulates lifespan in Caenorhabditis elegans. However, the mechanism by which H3K4me3 modifiers affect longevity, and whether this mechanism involves metabolic changes, remain unclear. Here we show that a deficiency in H3K4me3 methyltransferase, which extends lifespan, promotes fat accumulation in worms with a specific enrichment of mono-Unsaturated Fatty Acids (MUFAs). This fat metabolism switch in H3K4me3 methyltransferase-deficient worms is mediated at least in part by the downregulation of germline targets, including S6 kinase, and by the activation of an intestinal transcriptional network that upregulates delta-9 Fatty acid desaturases. Notably, the accumulation of MUFAs is necessary for the lifespan extension of H3K4me3 methyltransferase-deficient worms, and dietary MUFAs are sufficient to extend lifespan. Given the conservation of lipid metabolism, dietary or endogenous MUFAs could extend lifespan and healthspan in other species, including mammals.
Michael S Brown - One of the best experts on this subject based on the ideXlab platform.
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Unsaturated Fatty Acids inhibit transcription of the sterol regulatory element binding protein 1c srebp 1c gene by antagonizing ligand dependent activation of the lxr
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Jiafu Ou, Joseph L Goldstein, Hua Tu, Bei Shan, Russell A Deboseboyd, Yuriy K Bashmakov, Michael S BrownAbstract:Sterol regulatory element-binding protein-1c (SREBP-1c) enhances transcription of genes encoding enzymes of Unsaturated Fatty acid biosynthesis in liver. SREBP-1c mRNA is known to increase when cells are treated with agonists of liver X receptor (LXR), a nuclear hormone receptor, and to decrease when cells are treated with Unsaturated Fatty Acids, the end products of SREBP-1c action. Here we show that Unsaturated Fatty Acids lower SREBP-1c mRNA levels in part by antagonizing the actions of LXR. In cultured rat hepatoma cells, arachidonic acid and other Fatty Acids competitively inhibited activation of the endogenous SREBP-1c gene by an LXR ligand. Arachidonate also blocked the activation of a synthetic LXR-dependent promoter in transfected human embryonic kidney-293 cells. In vitro, arachidonate and other Unsaturated Fatty Acids competitively blocked activation of LXR, as reflected by a fluorescence polarization assay that measures ligand-dependent binding of LXR to a peptide derived from a coactivator. These data offer a potential mechanism that partially explains the long-known ability of dietary Unsaturated Fatty Acids to decrease the synthesis and secretion of Fatty Acids and triglycerides in livers of humans and other animals.
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Unsaturated Fatty Acids down regulate srebp isoforms 1a and 1c by two mechanisms in hek 293 cells
Journal of Biological Chemistry, 2001Co-Authors: Voe C Hannah, Jiafu Ou, Amber U Luong, Joseph L Goldstein, Michael S BrownAbstract:Abstract Sterol regulatory element-binding proteins (SREBPs) are membrane-bound transcription factors that increase the synthesis of Fatty Acids as well as cholesterol in animal cells. All three SREBP isoforms (SREBP-1a, -1c, and -2) are subject to feedback regulation by cholesterol, which blocks their proteolytic release from membranes. Previous data indicate that the SREBPs are also negatively regulated by Unsaturated Fatty Acids, but the mechanism is uncertain. In the current experiments, Unsaturated Fatty Acids decreased the nuclear content of SREBP-1, but not SREBP-2, in cultured human embryonic kidney (HEK)-293 cells. The potency of Unsaturated Fatty Acids increased with increasing chain length and degree of unsaturation. Oleate, linoleate, and arachidonate were all effective, but the saturated Fatty Acids palmitate and stearate were not effective. Down-regulation occurred at two levels. The mRNAs encoding SREBP-1a and SREBP-1c were markedly reduced, and the proteolytic processing of these SREBPs was inhibited. When SREBP-1a was produced by a cDNA expressed from an independent promoter, Unsaturated Fatty Acids reduced nuclear SREBP-1a without affecting the mRNA level. There was no effect when the cDNA encoded a truncated version that was not membrane-bound. When administered together, sterols and Unsaturated Fatty Acids potentiated each other in reducing nuclear SREBP-1. In the absence of Fatty Acids, sterols did not cause a sustained reduction of nuclear SREBP-1, but they did reduce nuclear SREBP-2. We conclude that Unsaturated Fatty Acids, as well as sterols, can down-regulate nuclear SREBPs and that Unsaturated Fatty Acids have their greatest inhibitory effects on SREBP-1a and SREBP-1c, whereas sterols have their greatest inhibitory effects on SREBP-2.
Bert Klein Gebbink - One of the best experts on this subject based on the ideXlab platform.
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transition metal catalyzed oxidative double bond cleavage of simple and bio derived alkenes and Unsaturated Fatty Acids
Catalysis Science & Technology, 2014Co-Authors: Peter Spannring, Pieter C A Bruijnincx, Bert M Weckhuysen, Bert Klein GebbinkAbstract:The oxidative cleavage of the CC double bond in Unsaturated Fatty Acids into aldehydes or carboxylic Acids is a reaction of current interest in biomass valorization. The products of this reaction, which is currently being performed on an industrial scale by means of ozonolysis, can be applied for the production of commodity chemicals such as plasticizers and polymers. Alternative, catalytic methods for this conversion that are not based on the hazardous ozone oxidant are of high interest. In this respect, the use of transition metal catalysts would allow the application of milder reaction conditions and more benign oxidants. This review covers the various transition metal-based catalysts that have been reported for the oxidative cleavage of alkenes in general and the cleavage of Unsaturated Fatty Acids in particular. Catalytic systems based on second- and third-row metals such as Ru, Os, and W have been widely studied and are well-known to catalyze the cleavage of various alkenes and Unsaturated Fatty Acids. In addition to simple metal salts, metal oxides or peroxides, various metal coordination complexes have been investigated for chemo- and regioselective olefin cleavage. Heterogeneous catalyst systems based on these metals have, in addition, been studied with a focus on catalyst reuse. To circumvent the use of expensive, toxic or less abundant second- and third-row metal catalysts, the use of first-row transition metal catalysts for the cleavage reaction might be preferred. However, examples of such catalysts for oxidative olefin cleavage are much less documented. The application of Fe- and Mn-based catalysts currently is largely limited to activated alkenes, e.g. styrene derivatives. The many possibilities that are offered by careful ligand design together with the recent advances in the field of first-row transition metal oxidation catalysis may allow for the development of catalyst systems that substitute ozone or second- and third-row metal catalysts for the oxidative cleavage of simple alkenes and Unsaturated Fatty Acids.
