Metabolite Signature of Simvastatin Treatment Involves Multiple Metabolic Pathways

Overview

Journal Metabolites

Publisher MDPI

Date 2022 Aug 25

PMID 36005625

Authors

Lilian Fernandes Silva

Rowmika Ravi

Jagadish Vangipurapu

Markku Laakso

Affiliations

Soon will be listed here.

Abstract

Statins inhibit the 3-hydroxy-3-methylglutaryl-CoA reductase enzyme and are the most widely used medication for hypercholesterolemia. Previous studies on the metabolite signature of simvastatin treatment have included only a small number of metabolites. We performed a high-throughput liquid chromatography-tandem mass spectroscopy profiling on the effects of simvastatin treatment on 1098 metabolite concentrations in the participants of the METSIM (Metabolic Syndrome In Men) study including 1332 participants with simvastatin treatment and 6200 participants without statin treatment. We found that simvastatin exerts profound pleiotropic effects on different metabolite pathways, affecting not only lipids, but also amino acids, peptides, nucleotides, carbohydrates, co-factors, vitamins, and xenobiotics. We identified 321 metabolites significantly associated with simvastatin treatment, and 313 of these metabolites were novel. Our study is the first comprehensive evaluation of the metabolic signature of simvastatin treatment in a large population-based study.

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References

McGregor G, Campbell A, Fey S, Tumanov S, Sumpton D, Blanco G . Targeting the Metabolic Response to Statin-Mediated Oxidative Stress Produces a Synergistic Antitumor Response. Cancer Res. 2019; 80(2):175-188. DOI: 10.1158/0008-5472.CAN-19-0644. View

Li L, Klett E, Coleman R . Acyl-CoA synthesis, lipid metabolism and lipotoxicity. Biochim Biophys Acta. 2009; 1801(3):246-51. PMC: 2824076. DOI: 10.1016/j.bbalip.2009.09.024. View

Loria P, Bertolotti M, Cassinadri M, Dilengite M, Bozzoli M, Carubbi F . Short-term effects of simvastatin on bile acid synthesis and bile lipid secretion in human subjects. Hepatology. 1994; 19(4):882-8. View

Swerdlow D, Preiss D, Kuchenbaecker K, Holmes M, Engmann J, Shah T . HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 2014; 385(9965):351-61. PMC: 4322187. DOI: 10.1016/S0140-6736(14)61183-1. View

WILKEN D, McMacken M, RODRIQUEZ A . Choline and betaine aldehyde oxidation by rat liver mitochondria. Biochim Biophys Acta. 1970; 216(2):305-17. DOI: 10.1016/0005-2728(70)90222-7. View

. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344(8934):1383-9. View

Schooling C, Au Yeung S, Freeman G, Cowling B . The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med. 2013; 11:57. PMC: 3621815. DOI: 10.1186/1741-7015-11-57. View

Su B, Ryan R . Metabolic biology of 3-methylglutaconic acid-uria: a new perspective. J Inherit Metab Dis. 2014; 37(3):359-68. PMC: 4016128. DOI: 10.1007/s10545-013-9669-0. View

Giurgea A, Margeta C, Maca T, Rezaie-Majd A, Bucek R, Manavi M . Simvastatin reduces serum level of vascular endothelial growth factor in hypercholesterolemic patients. J Cardiovasc Pharmacol. 2006; 47(1):30-6. DOI: 10.1097/01.fjc.0000191970.65998.7a. View

10.

Phillips P, Haas R, Bannykh S, Hathaway S, Gray N, Kimura B . Statin-associated myopathy with normal creatine kinase levels. Ann Intern Med. 2002; 137(7):581-5. DOI: 10.7326/0003-4819-137-7-200210010-00009. View

11.

Maltese W, Aprille J . Relation of mevalonate synthesis to mitochondrial ubiquinone content and respiratory function in cultured neuroblastoma cells. J Biol Chem. 1985; 260(21):11524-9. View

12.

Shiomi M, Yamada S, Ito T . Atheroma stabilizing effects of simvastatin due to depression of macrophages or lipid accumulation in the atheromatous plaques of coronary plaque-prone WHHL rabbits. Atherosclerosis. 2005; 178(2):287-94. DOI: 10.1016/j.atherosclerosis.2004.10.024. View

13.

Mihalik S, Goodpaster B, Kelley D, Chace D, Vockley J, Toledo F . Increased levels of plasma acylcarnitines in obesity and type 2 diabetes and identification of a marker of glucolipotoxicity. Obesity (Silver Spring). 2010; 18(9):1695-700. PMC: 3984458. DOI: 10.1038/oby.2009.510. View

14.

Kaddurah-Daouk R, Kristal B, Weinshilboum R . Metabolomics: a global biochemical approach to drug response and disease. Annu Rev Pharmacol Toxicol. 2008; 48:653-83. DOI: 10.1146/annurev.pharmtox.48.113006.094715. View

15.

Stamler J, Wentworth D, Neaton J . Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986; 256(20):2823-8. View

16.

Kanda H, Yokota K, Kohno C, Sawada T, Sato K, Yamaguchi M . Effects of low-dosage simvastatin on rheumatoid arthritis through reduction of Th1/Th2 and CD4/CD8 ratios. Mod Rheumatol. 2007; 17(5):364-8. DOI: 10.1007/s10165-007-0589-4. View

17.

Ludwig S, Dharmalingam S, Erickson-Nesmith S, Ren S, Zhu F, Ma G . Impact of simvastatin on hemostatic and fibrinolytic regulators in Type 2 diabetes mellitus. Diabetes Res Clin Pract. 2005; 70(2):110-8. DOI: 10.1016/j.diabres.2005.03.025. View

18.

Yanagita T, Yamamoto K, Ishida S, Sonda K, Morito F, Saku K . Effects of simvastatin, a cholesterol synthesis inhibitor, on phosphatidylcholine synthesis in HepG2 cells. Clin Ther. 1994; 16(2):200-8. View

19.

Fernandes Silva L, Vangipurapu J, Kuulasmaa T, Laakso M . An intronic variant in the GCKR gene is associated with multiple lipids. Sci Rep. 2019; 9(1):10240. PMC: 6629684. DOI: 10.1038/s41598-019-46750-3. View

20.

Laakso M, Kuusisto J . Diabetes Secondary to Treatment with Statins. Curr Diab Rep. 2017; 17(2):10. DOI: 10.1007/s11892-017-0837-8. View