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  • Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Nature communications (2022-05-11)
Alec G Trub, Gregory R Wagner, Kristin A Anderson, Scott B Crown, Guo-Fang Zhang, J Will Thompson, Olga R Ilkayeva, Robert D Stevens, Paul A Grimsrud, Rhushikesh A Kulkarni, Donald S Backos, Jordan L Meier, Matthew D Hirschey
ABSTRACT

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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Anti-HMG-CoA reductase Antibody, from rabbit, purified by affinity chromatography
Sigma-Aldrich
Monoclonal Anti-FASN antibody produced in mouse, clone 3F2-1F3, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Anti-HMG-Lysine, from rabbit