Statin therapy inhibits fatty acid synthase via dynamic protein modifications.

Autor: Trub AG; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA.; Department of Pharmacology & Cancer Biology, Durham, NC, USA., Wagner GR; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Durham, NC, USA., Anderson KA; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA.; Department of Pharmacology & Cancer Biology, Durham, NC, USA., Crown SB; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA., Zhang GF; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Durham, NC, USA., Thompson JW; Department of Pharmacology & Cancer Biology, Durham, NC, USA.; Duke Proteomics and Metabolomics Shared Resource, Duke University Medical Center, Durham, NC, 27710, USA., Ilkayeva OR; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Durham, NC, USA., Stevens RD; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA., Grimsrud PA; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA.; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Durham, NC, USA., Kulkarni RA; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA., Backos DS; Computational Chemistry and Biology Core Facility, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Anschutz Medical Campus, Aurora, CO, 80045, USA., Meier JL; Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, 21702, USA., Hirschey MD; Sarah W. Stedman Nutrition and Metabolism Center, Duke Molecular Physiology Institute, Durham, NC, USA. matthew.hirschey@duke.edu.; Department of Pharmacology & Cancer Biology, Durham, NC, USA. matthew.hirschey@duke.edu.; Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Durham, NC, USA. matthew.hirschey@duke.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 May 10; Vol. 13 (1), pp. 2542. Date of Electronic Publication: 2022 May 10.
DOI: 10.1038/s41467-022-30060-w
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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