The integral role of mTOR in lipid metabolism

Soliman, Ghada A.

doi:10.4161/cc.10.6.14930

Cited by 77 publications

(55 citation statements)

References 16 publications

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“…Furthermore, complex II is stimulated by FADH 2 , which is mainly derived from fatty-acid oxidation. mTOR metabolism has been previously described to be connected to lipid metabolism regulation (Laplante and Sabatini, 2012;Soliman, 2011). Moreover, levels of ketone bodies, carnitine metabolism and free fatty acids significantly differed between OreR and sm21 rapamycin-treated flies, suggesting that lipid oxidation is an important metabolic pathway that mediates the beneficial effects of rapamycin on mitochondrial physiology.…”

Section: Divergent Mitochondrial Genotypes On a Common Nuclear Backgrmentioning

confidence: 90%

“…This involves mTORC1-mediated phosphorylation of the eukaryotic initiation factor 4E binding protein 1 (eIF4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) in order to upregulate 59-cap-dependent protein translation (Richter and Sonenberg, 2005). In addition to modulation of protein translation, the mTOR pathway has also been implicated in cell growth, autophagy, longevity and metabolism (Finley and Haigis, 2009;Laplante and Sabatini, 2012;Soliman, 2011;Mathew and White, 2011), all key biological processes in health and homeostasis. Indeed, dysregulation of mTOR signaling is a common condition in human diseases (Dazert and Hall, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila

Villa-Cuesta

Holmbeck

Rand

2014

Journal of Cell Science

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Downregulation of the mammalian target of rapamycin (mTOR) pathway by its inhibitor rapamycin is emerging as a potential pharmacological intervention that mimics the beneficial effects of dietary restriction. Modulation of mTOR has diverse effects on mitochondrial metabolism and biogenesis, but the role of the mitochondrial genotype in mediating these effects remains unknown. Here, we use novel mitochondrial genome replacement strains in Drosophila to test the hypothesis that genes encoded in mitochondrial DNA (mtDNA) influence the mTOR pathway. We show that rapamycin increases mitochondrial respiration and succinate dehydrogenase activity, decreases H 2 O 2 production and generates distinct shifts in the metabolite profiles of isolated mitochondria versus whole Drosophila. These effects are disabled when divergent mitochondrial genomes from D. simulans are placed into a common nuclear background, demonstrating that the benefits of rapamycin to mitochondrial metabolism depend on genes encoded in the mtDNA. Rapamycin is able to enhance mitochondrial respiration when succinate dehydrogenase activity is blocked, suggesting that the beneficial effects of rapamycin on these two processes are independent. Overall, this study provides the first evidence for a link between mitochondrial genotype and the effects of rapamycin on mitochondrial metabolic pathways.

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Section: Divergent Mitochondrial Genotypes On a Common Nuclear Backgrmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila

Villa-Cuesta

Holmbeck

Rand

2014

Journal of Cell Science

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“…mTORC1 is highly activated in tissues of obese humans and HFD-fed rodents (19,41). Inhibition of mTORC1 promotes triacylglycerol lipolysis that releases free fatty acids, blocks adipogenesis, and impairs the maintenance of fat cells (42,43). Recent studies have demonstrated that the most common cancer-promoting signaling event that converges on mTORC1 is aberrant activation of Akt kinase (44).…”

Section: Discussionmentioning

confidence: 99%

Sirt1 decreased adipose inflammation by interacting with Akt2 and inhibiting mTOR/S6K1 pathway in mice

Liu¹,

Gan²,

Liu

et al. 2016

Journal of Lipid Research

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shown that Sirt1 is involved in regulation of inflammation response and inhibits inflammatory pathways in macrophages and dendritic cells (6, 7). In 3T3-L1 adipocytes, Sirt1 can attenuate TNF--induced insulin resistance and inflammation (3,8). Resveratrol (RES) is a natural polyphenolic compound known for its beneficial effects on energy homeostasis (9, 10). Studies have shown that RES attenuates inflammation of adipocytes and vascular endothelial cells by activating Sirt1 and inducing autophagy (11-13). However, the regulatory mechanism of RES on Sirt1 and adipose inflammation remains unclear.The Akt/mammalian target of rapamycin (mTOR) pathway plays an important role in the regulation of cellular gluconeogenesis and metabolism (14,15). mTOR is highly conserved serine/threonine kinase that is expressed in cancer cells, adipocytes, and hepatocytes, and can be directly phosphorylated by activated . During development of obesity, adipose pro-inflammatory responses are closely associated with the development of insulin resistance in adipose tissue (19,20). A recent study showed that phosphorylation of Akt in macrophages could activate mTOR signal and then led to inflammation and insulin resistance in high-fat diet (HFD)-induced obesity (21). Moreover, Pang et al. (22) reported that Sirt1 directly bound protein kinase B (Akt2) and then inhibited adipogenesis in porcine adipocytes. Busch et al. (23) also suggested that Akt was one of the main upstream stimulatory kinases that modulated by Sirt1. However, whether the interaction between Sirt1 and Akt2 can regulate adipose inflammation has not been studied.We suggested that RES would attenuate HFD-induced obesity and adipose inflammation by activating Sirt1. We found that RES promoted the interaction of Sirt1 and Akt2, and then inhibited adipose inflammation by activating the mTOR/S6K1 pathway. These findings identify a novel function of Sirt1 in the regulation of adipose inflammation Sirtuin type 1 (Sirt1) is a member of the silencing information regulator 2 (Sir2) family called sirtuins, and is wellknown for its deacetylation in regulation of gene silencing, energy homeostasis, and apoptosis (1-3). The overloaded calorie intake leads to dysfunction of adipocytes and causes obesity (4). Obesity is closely associated with chronic inflammation and characterized by abnormal cytokine production, increased acute-phase reactants, and an activated network of inflammatory signal pathways (5 Abbreviations: Akt2, protein kinase B; HFD, high-fat diet; IL-6, interleukin-6; iNOS, inducible nitric oxide synthase; mTOR, mammalian target of rapamycin; NAM, nicotinamide; RES, resveratrol; Sirt1, sirtuin type 1.

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“…As well as its role in normal cell growth, regulation of blood glucose homeostasis and lipid metabolism (10)(11)(12)(13)(14), the PI3K-AKT-mTOR pathway plays an important role in regulating the immune system and cytokines production by immune cells (15). Emerging data indicate that the inhibition of PI3K signaling reduces the generation and suppresses the secretion of proinflammatory cytokines and leads to an attenuated immune response (15)(16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

Rafii

Roda

Geuna

et al. 2015

Clinical Cancer Research

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Novel antitumor therapies against the PI3K-AKT-mTOR pathway are increasingly used to treat cancer, either as single agents or in combination with chemotherapy or other targeted therapies. Although these agents are not known to be myelosuppressive, an increased risk of infection has been reported with rapamycin analogs. However, the risk of infection with new inhibitors of this pathway such as PI3K, AKT, mTORC 1/2 or multi-kinase inhibitors is unknown. Methods In this retrospective case-control study, we determined the incidence of infection in a group of 432 patients who were treated on 15 phase I clinical trials involving PI3K-AKT-mTOR pathway inhibitors (cases) vs a group of 100 patients on 10 phase I clinical trials of single agent non-PI3K-AKT-mTOR pathway inhibitors (controls) which did not involve conventional cytotoxic agents. We also collected data from 42 patients who were treated with phase I trials of combinations of PI3K-AKT-mTOR inhibitors and MEK inhibitors and 24 patients with combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapies. Results The incidence of all grade infection was significantly higher with all single agent PI3K-AKT-mTOR inhibitors compared to the control group (27% vs 8% respectively, OR: 4.26, 95% CI: 1.9-9.1, p=0.0001). The incidence of grade 3 and 4 infection was also significantly higher with PI3K-AKT-mTOR inhibitors compared to the control group (10.3% vs 3%, OR: 3.74, 95% CI: 1.1-12.4, p=0.02). Also the combination of PI3K-AKT-mTOR inhibitors and chemotherapy was associated with a significantly higher incidence of all grade (OR: 4.79, 95% CI: 2.0-11.2, p=0.0001) and high grade (OR: 2.87, 95% CI: 1.0-7.6, p=0.03) infection when compared with single agent PI3K-AKT-mTOR inhibitors. Conclusion Inhibitors of the PI3K-AKT-mTOR pathway can be associated with a higher risk of infection. Combinations of PI3K-AKT-mTOR inhibitors and cytotoxic chemotherapy significantly increase the risk of infection. This should be taken into consideration during the design and conduct of trials involving PI3K-AKT-mTOR pathway inhibitors, particularly when combined with chemotherapy or myelosuppressive agents.

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The integral role of mTOR in lipid metabolism

Cited by 77 publications

References 16 publications

Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila

Rapamycin increases mitochondrial efficiency by mtDNA-dependent reprogramming of mitochondrial metabolism in Drosophila

Sirt1 decreased adipose inflammation by interacting with Akt2 and inhibiting mTOR/S6K1 pathway in mice

Higher Risk of Infections with PI3K–AKT–mTOR Pathway Inhibitors in Patients with Advanced Solid Tumors on Phase I Clinical Trials

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