The multifaceted role of mTORC1 in the control of lipid metabolism

Ricoult, Stéphane J. H.; Manning, Brendan D.

doi:10.1038/embor.2013.5

Cited by 225 publications

(198 citation statements)

References 93 publications

(140 reference statements)

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“…The emerging role of mTORC1 in lipid homeostasis has captured the attention of many labs involved in the metabolic research (42,43). In particular, we have recently shown that mTORC1 mediates the effect of insulin on lipolysis in mammalian adipocytes by suppressing the expression of the rate-limiting lipase, ATGL, at the level of transcription (6).…”

Section: Discussionmentioning

confidence: 99%

4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL

Singh¹,

Shin²,

Yang

et al. 2015

Journal of Biological Chemistry

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Background: Insulin suppresses lipolysis in adipocytes by inducing Egr1 that inhibits expression of ATGL. Results: Stimulation of mTORC1 or genetic ablation of 4E-BP1/2 increase expression of Egr1 regardless of its mRNA levels. Conclusion: Regulation of Egr1 by insulin takes place predominantly at the level of translation via mTORC1/4E-BP. Significance: Translational control of the Egr1 expression explains the role of mTORC1 in regulation of lipolysis.

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Section: Discussionmentioning

confidence: 99%

4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL

Singh¹,

Shin²,

Yang

et al. 2015

Journal of Biological Chemistry

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“…S11B). Next to the transcriptional program of the adipogenesis, mTORC1 controls the balance between lipogenesis and lipolysis in adipocytes (46). Essential proteins for the LD accumulation and thus, the initiation of lipid storage and lipogenesis are substrates of the mTORC1 as, for example, lipin-1 (47).…”

Section: Discussionmentioning

confidence: 99%

In situ characterization of the mTORC1 during adipogenesis of human adult stem cells on chip

Schneider

Platen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mammalian target of rapamycin (mTOR) is a central kinase integrating nutrient, energy, and metabolite signals. The kinase forms two distinct complexes: mTORC1 and mTORC2. mTORC1 plays an essential but undefined regulatory function for regeneration of adipose tissue. Analysis of mTOR in general is hampered by the complexity of regulatory mechanisms, including protein interactions and/or phosphorylation, in an ever-changing cellular microenvironment. Here, we developed a microfluidic large-scale integration chip platform for culturing and differentiating human adiposederived stem cells (hASCs) in 128 separated microchambers under standardized nutrient conditions over 3 wk. The progression of the stem cell differentiation was measured by determining the lipid accumulation rates in hASC cultures. For in situ protein analytics, we developed a multiplex in situ proximity ligation assay (mPLA) that can detect mTOR in its two complexes selectively in single cells and implemented it on the same chip. With this combined technology, it was possible to reveal that the mTORC1 is regulated in its abundance, phosphorylation state, and localization in coordination with lysosomes during adipogenesis. High-content image analysis and parameterization of the in situ PLA signals in over 1 million cells cultured on four individual chips showed that mTORC1 and lysosomes are temporally and spatially coordinated but not in its composition during adipogenesis.microfluidics | stem cell differentiation | adipogenesis | mTORC1 regulation | multiplexed PLA

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“…Membrane lipid homeostasis regulated by ORP5 and other lipid transfer proteins has an impact on mTORC1, which itself is a key regulator of lipid metabolism, as well as protein synthesis and cell proliferation (4). Notably, ORP5 appears to be a phosphatidylserine transporter (14) and has been shown to deliver phosphatidylserine from the ER to the plasma membrane and mitochondria (15)(16)(17).…”

Section: Orp5 Depletion Impairs the Localization Of Mtor To Lysosomesmentioning

confidence: 99%

“…In this regard, activated mTORC1 phosphorylates and activates its major downstream effector ribosomal protein S6 kinase (S6K). Once activated, S6K phosphorylates the ribosomal S6 protein to control fundamental cellular processes including protein synthesis, lipid metabolism, and cell proliferation (3,4).…”

Section: Introductionmentioning

confidence: 99%

Oxysterol-binding protein–related protein 5 (ORP5) promotes cell proliferation by activation of mTORC1 signaling

Zadoorian

Lukmantara

et al. 2018

Journal of Biological Chemistry

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Oxysterol-binding protein (OSBP) and OSBPrelated proteins (ORPs) constitute a large family of proteins that mainly function in lipid transport and sensing. ORP5 is an endoplasmic reticulum (ER)-anchored protein implicated in lipid transfer at the contact sites between the ER and other membranes. Recent studies indicate that ORP5 is also involved in cancer cell invasion and tumor progression. However, the molecular mechanism underlying ORP5's involvement in cancer is unclear. Here, we report that ORP5 promotes cell proliferation and motility of HeLa cells, an effect that depends on its functional OSBP-related domain (ORD). We also found that ORP5 depletion or substitutions of key residues located within ORP5-ORD and responsible for interactions with lipids interfered with cell proliferation, migration and invasion. ORP5 interacted with the protein mechanistic target of rapamycin (mTOR), and this interaction also required ORP5-ORD. Of note, whereas ORP5 overexpression induced mTOR complex 1 (mTORC1) activity, ORP5 down-regulation had the opposite effect. Finally, ORP5-depleted cells exhibited impaired mTOR localization to lysosomes, which may have accounted for the blunted mTORC1 activation. Together, our results suggest that ORP5 expression is positively correlated with mTORC1 signaling and that ORP5 stimulates cell proliferation, at least in part, by activating mTORC1.

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The multifaceted role of mTORC1 in the control of lipid metabolism

Cited by 225 publications

References 93 publications

4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL

4E-BPs Control Fat Storage by Regulating the Expression of Egr1 and ATGL

In situ characterization of the mTORC1 during adipogenesis of human adult stem cells on chip

Oxysterol-binding protein–related protein 5 (ORP5) promotes cell proliferation by activation of mTORC1 signaling

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