Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • May 10, 2022

Published In

Volume / Issue

  • 13 / 1

Start / End Page

  • 2542 -

PubMed ID

  • 35538051

Pubmed Central ID

  • PMC9090928

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-022-30060-w

Language

  • eng