Statin Therapy Inhibits Fatty Acid Synthase Via Dynamic Protein Modifications

Overview

Journal Nat Commun

Specialty Biology

Date 2022 May 10

PMID 35538051

Authors

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

Affiliations

Soon will be listed here.

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.

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References

Leighty R, Antoniewicz M . COMPLETE-MFA: complementary parallel labeling experiments technique for metabolic flux analysis. Metab Eng. 2013; 20:49-55. DOI: 10.1016/j.ymben.2013.08.006. View

Kumai T, Matsumoto N, Koitabashi Y, Takeba Y, Oonuma S, Sekine S . Pleiotropic effects of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors: candidate mechanisms for anti-lipid deposition in blood vessels. Curr Med Chem Cardiovasc Hematol Agents. 2005; 3(3):195-201. DOI: 10.2174/1568016054368223. View

Funai K, Song H, Yin L, Lodhi I, Wei X, Yoshino J . Muscle lipogenesis balances insulin sensitivity and strength through calcium signaling. J Clin Invest. 2013; 123(3):1229-40. PMC: 3582136. DOI: 10.1172/JCI65726. View

Antoniewicz M, Kelleher J, Stephanopoulos G . Elementary metabolite units (EMU): a novel framework for modeling isotopic distributions. Metab Eng. 2006; 9(1):68-86. PMC: 1994654. DOI: 10.1016/j.ymben.2006.09.001. View

. The Gene Ontology resource: enriching a GOld mine. Nucleic Acids Res. 2020; 49(D1):D325-D334. PMC: 7779012. DOI: 10.1093/nar/gkaa1113. View

Leighty R, Antoniewicz M . Parallel labeling experiments with [U-13C]glucose validate E. coli metabolic network model for 13C metabolic flux analysis. Metab Eng. 2012; 14(5):533-41. DOI: 10.1016/j.ymben.2012.06.003. View

Pencina M, Navar-Boggan A, DAgostino Sr R, Williams K, Neely B, Sniderman A . Application of new cholesterol guidelines to a population-based sample. N Engl J Med. 2014; 370(15):1422-31. DOI: 10.1056/NEJMoa1315665. View

Crown S, Long C, Antoniewicz M . Integrated 13C-metabolic flux analysis of 14 parallel labeling experiments in Escherichia coli. Metab Eng. 2015; 28:151-158. PMC: 5845449. DOI: 10.1016/j.ymben.2015.01.001. View

Wadke M, Brunengraber H, Lowenstein J, Dolhun J, Arsenault G . Fatty acid synthesis by liver perfused with deuterated and tritiated water. Biochemistry. 1973; 12(14):2619-24. DOI: 10.1021/bi00738a011. View

10.

Smith P, Krohn R, Hermanson G, Mallia A, Gartner F, Provenzano M . Measurement of protein using bicinchoninic acid. Anal Biochem. 1985; 150(1):76-85. DOI: 10.1016/0003-2697(85)90442-7. View

11.

Jungas R . Fatty acid synthesis in adipose tissue incubated in tritiated water. Biochemistry. 1968; 7(10):3708-17. DOI: 10.1021/bi00850a050. View

12.

Jensen K, Previs S, Zhu L, Herath K, Wang S, Bhat G . Demonstration of diet-induced decoupling of fatty acid and cholesterol synthesis by combining gene expression array and 2H2O quantification. Am J Physiol Endocrinol Metab. 2011; 302(2):E209-17. DOI: 10.1152/ajpendo.00436.2011. View

13.

Meier J, Patel A, Niessen S, Meehan M, Kersten R, Yang J . Practical 4'-phosphopantetheine active site discovery from proteomic samples. J Proteome Res. 2010; 10(1):320-9. PMC: 3042426. DOI: 10.1021/pr100953b. View

14.

Gao L, Chiou W, Tang H, Cheng X, Camp H, Burns D . Simultaneous quantification of malonyl-CoA and several other short-chain acyl-CoAs in animal tissues by ion-pairing reversed-phase HPLC/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2007; 853(1-2):303-13. DOI: 10.1016/j.jchromb.2007.03.029. View

15.

Jensen-Urstad A, Song H, Lodhi I, Funai K, Yin L, Coleman T . Nutrient-dependent phosphorylation channels lipid synthesis to regulate PPARα. J Lipid Res. 2013; 54(7):1848-59. PMC: 3679387. DOI: 10.1194/jlr.M036103. View

16.

Anderson K, Huynh F, Fisher-Wellman K, Stuart J, Peterson B, Douros J . SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion. Cell Metab. 2017; 25(4):838-855.e15. PMC: 5444661. DOI: 10.1016/j.cmet.2017.03.003. View

17.

Crown S, Antoniewicz M . Parallel labeling experiments and metabolic flux analysis: Past, present and future methodologies. Metab Eng. 2012; 16:21-32. PMC: 6474253. DOI: 10.1016/j.ymben.2012.11.010. View

18.

Antoniewicz M . Parallel labeling experiments for pathway elucidation and (13)C metabolic flux analysis. Curr Opin Biotechnol. 2015; 36:91-7. DOI: 10.1016/j.copbio.2015.08.014. View

19.

Chen E, Tan C, Kou Y, Duan Q, Wang Z, Meirelles G . Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool. BMC Bioinformatics. 2013; 14:128. PMC: 3637064. DOI: 10.1186/1471-2105-14-128. View

20.

Maier J, Martinez C, Kasavajhala K, Wickstrom L, Hauser K, Simmerling C . ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB. J Chem Theory Comput. 2015; 11(8):3696-713. PMC: 4821407. DOI: 10.1021/acs.jctc.5b00255. View