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Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Publication ,  Journal Article
Trub, AG; Wagner, GR; Anderson, KA; Crown, SB; Zhang, G-F; Thompson, JW; Ilkayeva, OR; Stevens, RD; Grimsrud, PA; Kulkarni, RA; Backos, DS ...
Published in: Nat Commun
May 10, 2022

Statins are a class of drug widely prescribed for the prevention of cardiovascular disease, with pleiotropic cellular effects. Statins inhibit HMG-CoA reductase (HMGCR), which converts the metabolite HMG-CoA into mevalonate. Recent discoveries have shown HMG-CoA is a reactive metabolite that can non-enzymatically modify proteins and impact their activity. Therefore, we predicted that inhibition of HMGCR by statins might increase HMG-CoA levels and protein modifications. Upon statin treatment, we observe a strong increase in HMG-CoA levels and modification of only a single protein. Mass spectrometry identifies this protein as fatty acid synthase (FAS), which is modified on active site residues and, importantly, on non-lysine side-chains. The dynamic modifications occur only on a sub-pool of FAS that is located near HMGCR and alters cellular signaling around the ER and Golgi. These results uncover communication between cholesterol and lipid biosynthesis by the substrate of one pathway inhibiting another in a rapid and reversible manner.

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Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

May 10, 2022

Volume

13

Issue

1

Start / End Page

2542

Location

England

Related Subject Headings

  • Mevalonic Acid
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hydroxymethylglutaryl CoA Reductases
  • Humans
  • Fatty Acid Synthases
  • Cholesterol
  • Cardiovascular Diseases
 

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Trub, A. G., Wagner, G. R., Anderson, K. A., Crown, S. B., Zhang, G.-F., Thompson, J. W., … Hirschey, M. D. (2022). Statin therapy inhibits fatty acid synthase via dynamic protein modifications. Nat Commun, 13(1), 2542. https://doi.org/10.1038/s41467-022-30060-w
Trub, Alec G., Gregory R. Wagner, Kristin A. Anderson, Scott B. Crown, Guo-Fang Zhang, J Will Thompson, Olga R. Ilkayeva, et al. “Statin therapy inhibits fatty acid synthase via dynamic protein modifications.Nat Commun 13, no. 1 (May 10, 2022): 2542. https://doi.org/10.1038/s41467-022-30060-w.
Trub AG, Wagner GR, Anderson KA, Crown SB, Zhang G-F, Thompson JW, et al. Statin therapy inhibits fatty acid synthase via dynamic protein modifications. Nat Commun. 2022 May 10;13(1):2542.
Trub, Alec G., et al. “Statin therapy inhibits fatty acid synthase via dynamic protein modifications.Nat Commun, vol. 13, no. 1, May 2022, p. 2542. Pubmed, doi:10.1038/s41467-022-30060-w.
Trub AG, Wagner GR, Anderson KA, Crown SB, Zhang G-F, Thompson JW, Ilkayeva OR, Stevens RD, Grimsrud PA, Kulkarni RA, Backos DS, Meier JL, Hirschey MD. Statin therapy inhibits fatty acid synthase via dynamic protein modifications. Nat Commun. 2022 May 10;13(1):2542.

Published In

Nat Commun

DOI

EISSN

2041-1723

Publication Date

May 10, 2022

Volume

13

Issue

1

Start / End Page

2542

Location

England

Related Subject Headings

  • Mevalonic Acid
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Hydroxymethylglutaryl CoA Reductases
  • Humans
  • Fatty Acid Synthases
  • Cholesterol
  • Cardiovascular Diseases