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Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation.

Cell metabolism | 2018

The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.

Pubmed ID: 30146486 RIS Download

Research resources used in this publication

Additional research tools detected in this publication

None found

Antibodies used in this publication

Associated grants

  • Agency: Intramural NIH HHS, United States
    Id: ZIA BC011488

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


Raptor (24C12) Rabbit mAb (antibody)

RRID:AB_561245

This monoclonal targets Raptor (24C12) Rabbit mAb

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G L (86B8) Rabbit mAb (antibody)

RRID:AB_823685

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Anti-4E-BP1, phospho (Thr37 / Thr46) Monoclonal Antibody (antibody)

RRID:AB_560835

This monoclonal targets 4E-BP1, phospho (Thr37 / Thr46)

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Na,K-ATPase alpha Antibody (antibody)

RRID:AB_2060983

This polyclonal targets Na,K-ATPase alpha 1

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Anti-NG2 Chondroitin Sulfate Proteoglycan (antibody)

RRID:AB_11213678

This polyclonal targets NG2 Chondroitin Sulfate Proteoglycan

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p70 S6 Kinase Antibody (antibody)

RRID:AB_331676

This polyclonal targets p70 S6 Kinase

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alpha-Tubulin Antibody (antibody)

RRID:AB_2210548

This polyclonal targets alpha-Tubulin

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Phospho-p70 S6 Kinase (Thr389) Antibody (antibody)

RRID:AB_330944

This polyclonal targets Phospho-p70 S6 Kinase (Thr389)

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Pan anti-malonyllysine antibody (antibody)

RRID:AB_2687947

This polyclonal targets malonyllysine

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Fatty Acid Synthase antibody (antibody)

RRID:AB_10697253

This polyclonal targets Fatty Acid Synthase antibody

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Akt Antibody (antibody)

RRID:AB_329827

This polyclonal targets Akt

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Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb (antibody)

RRID:AB_916156

This monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb

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Acetyl-CoA Carboxylase Antibody (antibody)

RRID:AB_2219400

This polyclonal targets Acetyl CoA Carboxylase

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Phospho-AMPKα (Thr172) Antibody (antibody)

RRID:AB_330330

This polyclonal targets Phospho-AMPKα (Thr172)

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4E-BP1 Antibody (antibody)

RRID:AB_331692

This polyclonal targets 4E-BP1

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Phospho-Akt (Ser473) (193H12) Rabbit mAb (antibody)

RRID:AB_331168

This monoclonal targets Phospho-Akt (Ser473) (193H12) Rabbit mAb

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Anti-rabbit IgG, HRP-linked Antibody (antibody)

RRID:AB_2099233

This polyclonal secondary targets IgG

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Fatty Acid Synthase (A-5) (antibody)

RRID:AB_2231427

This monoclonal targets Fatty Acid Synthase (A-5)

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RABBIT ANTI MOUSE COLLAGEN IV (antibody)

RRID:AB_2082660

This polyclonal targets Col4a3

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β-Actin (13E5) Rabbit mAb (antibody)

RRID:AB_2223172

This monoclonal targets beta-Actin

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Rictor (D16H9) Rabbit mAb (antibody)

RRID:AB_10612959

This monoclonal targets Rictor (D16H9) Rabbit mAb

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ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

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GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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edgeR (software resource)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

View all literature mentions

RStudio (software resource)

RRID:SCR_000432

Open source and enterprise ready professional software for R statistical computing environment. Integrated development environment for R. Includes console, syntax highlighting editor that supports direct code execution, as well as tools for plotting, history, debugging and workspace management. Available in open source and commercial editions and runs on desktop Windows, Mac, and Linux or in browser connected to RStudio Server or RStudio Server Pro (Debian/Ubuntu, RedHat/CentOS, and SUSE Linux).

View all literature mentions

Adobe Illustrator (software resource)

RRID:SCR_010279

Vector graphics software to create digital graphics, illustrations, and typography for several types of media: print, web, interactive, video, and mobile.

View all literature mentions

Fiji (software resource)

RRID:SCR_002285

Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.

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Imaris (software resource)

RRID:SCR_007370

Imaris provides range of capabilities for working with three dimensional images. Uses flexible editing and processing functions, such as interactive surface rendering and object slicing capabilities. And output to standard TIFF, Quicktime and AVI formats. Imaris accepts virtually all image formats that are used in confocal microscopy and many of those used in wide-field image acquisition.

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FlowJo (software resource)

RRID:SCR_008520

Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.

View all literature mentions

Phospho-Akt (Ser473) (193H12) Rabbit mAb (antibody)

RRID:AB_331168

This monoclonal targets Phospho-Akt (Ser473) (193H12) Rabbit mAb

View all literature mentions

4E-BP1 Antibody (antibody)

RRID:AB_331692

This polyclonal targets 4E-BP1

View all literature mentions

RStudio (software resource)

RRID:SCR_000432

Open source and enterprise ready professional software for R statistical computing environment. Integrated development environment for R. Includes console, syntax highlighting editor that supports direct code execution, as well as tools for plotting, history, debugging and workspace management. Available in open source and commercial editions and runs on desktop Windows, Mac, and Linux or in browser connected to RStudio Server or RStudio Server Pro (Debian/Ubuntu, RedHat/CentOS, and SUSE Linux).

View all literature mentions

Imaris (software resource)

RRID:SCR_007370

Imaris provides range of capabilities for working with three dimensional images. Uses flexible editing and processing functions, such as interactive surface rendering and object slicing capabilities. And output to standard TIFF, Quicktime and AVI formats. Imaris accepts virtually all image formats that are used in confocal microscopy and many of those used in wide-field image acquisition.

View all literature mentions

Fiji (software resource)

RRID:SCR_002285

Software package as distribution of ImageJ and ImageJ2 together with Java, Java3D and plugins organized into coherent menu structure. Used to assist research in life sciences.

View all literature mentions

GraphPad Prism (software resource)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

View all literature mentions

FlowJo (software resource)

RRID:SCR_008520

Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.

View all literature mentions

edgeR (software resource)

RRID:SCR_012802

Bioconductor software package for Empirical analysis of Digital Gene Expression data in R. Used for differential expression analysis of RNA-seq and digital gene expression data with biological replication.

View all literature mentions

ImageJ (software resource)

RRID:SCR_003070

Open source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.

View all literature mentions

Adobe Illustrator (software resource)

RRID:SCR_010279

Vector graphics software to create digital graphics, illustrations, and typography for several types of media: print, web, interactive, video, and mobile.

View all literature mentions

Acetyl-CoA Carboxylase Antibody (antibody)

RRID:AB_2219400

This polyclonal targets Acetyl CoA Carboxylase

View all literature mentions

Anti-4E-BP1, phospho (Thr37 / Thr46) Monoclonal Antibody (antibody)

RRID:AB_560835

This monoclonal targets 4E-BP1, phospho (Thr37 / Thr46)

View all literature mentions

Akt Antibody (antibody)

RRID:AB_329827

This polyclonal targets Akt

View all literature mentions

β-Actin (13E5) Rabbit mAb (antibody)

RRID:AB_2223172

This monoclonal targets beta-Actin

View all literature mentions

RABBIT ANTI MOUSE COLLAGEN IV (antibody)

RRID:AB_2082660

This polyclonal targets Col4a3

View all literature mentions

Phospho-AMPKα (Thr172) Antibody (antibody)

RRID:AB_330330

This polyclonal targets Phospho-AMPKα (Thr172)

View all literature mentions

alpha-Tubulin Antibody (antibody)

RRID:AB_2210548

This polyclonal targets alpha-Tubulin

View all literature mentions

Fatty Acid Synthase antibody (antibody)

RRID:AB_10697253

This polyclonal targets Fatty Acid Synthase antibody

View all literature mentions

Fatty Acid Synthase (A-5) (antibody)

RRID:AB_2231427

This monoclonal targets Fatty Acid Synthase (A-5)

View all literature mentions

G L (86B8) Rabbit mAb (antibody)

RRID:AB_823685

This monoclonal targets G L (86B8) Rabbit mAb

View all literature mentions

Anti-rabbit IgG, HRP-linked Antibody (antibody)

RRID:AB_2099233

This polyclonal secondary targets IgG

View all literature mentions

Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb (antibody)

RRID:AB_916156

This monoclonal targets Phospho-S6 Ribosomal Protein (Ser235/236) (D57.2.2E) XP Rabbit mAb

View all literature mentions

Rictor (D16H9) Rabbit mAb (antibody)

RRID:AB_10612959

This monoclonal targets Rictor (D16H9) Rabbit mAb

View all literature mentions

Raptor (24C12) Rabbit mAb (antibody)

RRID:AB_561245

This monoclonal targets Raptor (24C12) Rabbit mAb

View all literature mentions

p70 S6 Kinase Antibody (antibody)

RRID:AB_331676

This polyclonal targets p70 S6 Kinase

View all literature mentions

Phospho-p70 S6 Kinase (Thr389) Antibody (antibody)

RRID:AB_330944

This polyclonal targets Phospho-p70 S6 Kinase (Thr389)

View all literature mentions

Anti-NG2 Chondroitin Sulfate Proteoglycan (antibody)

RRID:AB_11213678

This polyclonal targets NG2 Chondroitin Sulfate Proteoglycan

View all literature mentions

Na,K-ATPase alpha Antibody (antibody)

RRID:AB_2060983

This polyclonal targets Na,K-ATPase alpha 1

View all literature mentions

Pan anti-malonyllysine antibody (antibody)

RRID:AB_2687947

This polyclonal targets malonyllysine

View all literature mentions