Statin therapy inhibits fatty acid synthase via dynamic protein modifications

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 and Matthew D. Hirschey ()
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Alec G. Trub: Duke Molecular Physiology Institute
Gregory R. Wagner: Duke Molecular Physiology Institute
Kristin A. Anderson: Duke Molecular Physiology Institute
Scott B. Crown: Duke Molecular Physiology Institute
Guo-Fang Zhang: Duke Molecular Physiology Institute
J. Will Thompson: Department of Pharmacology & Cancer Biology
Olga R. Ilkayeva: Duke Molecular Physiology Institute
Robert D. Stevens: Duke Molecular Physiology Institute
Paul A. Grimsrud: Duke Molecular Physiology Institute
Rhushikesh A. Kulkarni: National Institutes of Health
Donald S. Backos: University of Colorado, Anschutz Medical Campus
Jordan L. Meier: National Institutes of Health
Matthew D. Hirschey: Duke Molecular Physiology Institute

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-30060-w

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