Impairment of Angiogenesis by Fatty Acid Synthase Inhibition Involves mTOR Malonylation

Ulrike Bruning, Francisco Morales-Rodriguez, Joanna Kalucka, Jermaine Goveia, Federico Taverna, Karla C.S. Queiroz, Charlotte Dubois, Anna Rita Cantelmo, Rongyuan Chen, Stefan Loroch, Evy Timmerman, Vanessa Caixeta, Katarzyna Bloch, Lena Christin Conradi, Lucas Treps, An Staes, Kris Gevaert, Andrew Tee, Mieke Dewerchin, Clay F. SemenkovichFrancis Impens, Birgit Schilling, Eric Verdin, Johannes V. Swinnen, Jordan L. Meier, Rhushikesh A. Kulkarni, Albert Sickmann, Bart Ghesquière, Luc Schoonjans, Xuri Li, Massimiliano Mazzone, Peter Carmeliet

Research output: Contribution to journalArticlepeer-review

72 Scopus citations

Abstract

The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASN KD ) 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, FASN KD 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 FASN KD 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.

Original languageEnglish
Pages (from-to)866-880.e15
JournalCell metabolism
Volume28
Issue number6
DOIs
StatePublished - Dec 4 2018

Keywords

  • angiogenesis
  • endothelial cell
  • fatty acid synthase
  • lipids
  • mTOR
  • mTORC1
  • malonyl-CoA
  • metabolism
  • post-translational modifications
  • protein malonylation

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