Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia
Peter J Meikle, Gerard Wong, Ricardo Tan, Philippe Giral, Paul Robillard, Alexina Orsoni, Neil Hounslow, Dianna J Magliano, Jonathan E Shaw, Joanne E Curran, John Blangero, Bronwyn A Kingwell, M John Chapman, Peter J Meikle, Gerard Wong, Ricardo Tan, Philippe Giral, Paul Robillard, Alexina Orsoni, Neil Hounslow, Dianna J Magliano, Jonathan E Shaw, Joanne E Curran, John Blangero, Bronwyn A Kingwell, M John Chapman
Abstract
The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (-41%), remnant cholesterol (-55%), and LDL-cholesterol (-39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D.
Trial registration: ClinicalTrials.gov NCT01595828.
Keywords: cholesterol; lipidomics; metabolic syndrome; obesity; omega-3 fatty acids; pitavastatin; plasmalogens.
Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
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References
- Baigent C., Blackwell L., Emberson J., Holland L. E., Reith C., Bhala N., Peto R., Barnes E. H., Keech A., Simes J., et al. . 2010. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 376: 1670–1681.
- Nicholls S. J., Ballantyne C. M., Barter P. J., Chapman M. J., Erbel R. M., Libby P., Raichlen J. S., Uno K., Borgman M., Wolski K., et al. . 2011. Effect of two intensive statin regimens on progression of coronary disease. N. Engl. J. Med. 365: 2078–2087.
- Sposito A. C., and Chapman M. J.. 2002. Statin therapy in acute coronary syndromes: mechanistic insight into clinical benefit. Arterioscler. Thromb. Vasc. Biol. 22: 1524–1534.
- Kashani A., Phillips C. O., Foody J. M., Wang Y., Mangalmurti S., Ko D. T., and Krumholz H. M.. 2006. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 114: 2788–2797.
- Ridker P. M., Pradhan A., MacFadyen J. G., Libby P., and Glynn R. J.. 2012. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 380: 565–571.
- Waters D. D., Ho J. E., Boekholdt S. M., DeMicco D. A., Kastelein J. J., Messig M., Breazna A., and Pedersen T. R.. 2013. Cardiovascular event reduction versus new-onset diabetes during atorvastatin therapy: effect of baseline risk factors for diabetes. J. Am. Coll. Cardiol. 61: 148–152.
- Alberti G., Zimmet P., Shaw J., and Grundy S. M.. 2006. The IDF consensus worldwide definition of the metabolic sybdrome. IDF Communications. Accessed October 31, 2015 at .
- Chapman M. J., Ginsberg H. N., Amarenco P., Andreotti F., Boren J., Catapano A. L., Descamps O. S., Fisher E., Kovanen P. T., Kuivenhoven J. A., et al. . 2011. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur. Heart J. 32: 1345–1361.
- Li N., Fu J., Koonen D. P., Kuivenhoven J. A., Snieder H., and Hofker M. H.. 2014. Are hypertriglyceridemia and low HDL causal factors in the development of insulin resistance? Atherosclerosis. 233: 130–138.
- Cederberg H., Stancakova A., Yaluri N., Modi S., Kuusisto J., and Laakso M.. 2015. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. Diabetologia. 58: 1109–1117.
- Swerdlow D. I., Preiss D., Kuchenbaecker K. B., Holmes M. V., Engmann J. E., Shah T., Sofat R., Stender S., Johnson P. C., Scott R. A., et al. . 2015. HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials. Lancet. 385: 351–361.
- Naci H., Brugts J., and Ades T.. 2013. Comparative tolerability and harms of individual statins: a study-level network meta-analysis of 246,955 participants from 135 randomized, controlled trials. Circ. Cardiovasc. Qual. Outcomes. 6: 390–399.
- Navarese E. P., Buffon A., Andreotti F., Kozinski M., Welton N., Fabiszak T., Caputo S., Grzesk G., Kubica A., Swiatkiewicz I., et al. . 2013. Meta-analysis of impact of different types and doses of statins on new-onset diabetes mellitus. Am. J. Cardiol. 111: 1123–1130.
- Sattar N. A., Ginsberg H., Ray K., Chapman M. J., Arca M., Averna M., Betteridge D. J., Bhatnagar D., Bilianou E., Carmena R., et al. . 2014. The use of statins in people at risk of developing diabetes mellitus: evidence and guidance for clinical practice. Atheroscler. Suppl. 15: 1–15.
- Vallejo-Vaz A. J., Kondapally Seshasai S. R., Kurogi K., Michishita I., Nozue T., Sugiyama S., Tsimikas S., Yoshida H., and Ray K. K.. 2015. Effect of pitavastatin on glucose, HbA1c and incident diabetes: a meta-analysis of randomized controlled clinical trials in individuals without diabetes. Atherosclerosis. 241: 409–418.
- Chapman M. J., Le Goff W., Guerin M., and Kontush A.. 2010. Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors. Eur. Heart J. 31: 149–164.
- Meikle P. J., Wong G., Barlow C. K., Weir J. M., Greeve M. A., Macintosh G. L., Almasy L., Comuzzie A. G., Mahaney M. C., Kowalczyk A., et al. . 2013. Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS One. 8: e74341.
- Ståhlman M., Fagerberg B., Adiels M., Ekroos K., Chapman J. M., Kontush A., and Boren J.. 2013. Dyslipidemia, but not hyperglycemia and insulin resistance, is associated with marked alterations in the HDL lipidome in type 2 diabetic subjects in the DIWA cohort: impact on small HDL particles. Biochim. Biophys. Acta. 1831: 1609–1617.
- Boon J., Hoy A. J., Stark R., Brown R. D., Meex R. C., Henstridge D. C., Schenk S., Meikle P. J., Horowitz J. F., Kingwell B. A., et al. . 2013. Ceramides contained in LDL are elevated in type 2 diabetes and promote inflammation and skeletal muscle insulin resistance. Diabetes. 62: 401–410.
- de Mello V. D., Lankinen M., Schwab U., Kolehmainen M., Lehto S., Seppanen-Laakso T., Oresic M., Pulkkinen L., Uusitupa M., and Erkkila A. T.. 2009. Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia. 52: 2612–2615.
- Meikle P. J., Wong G., Barlow C. K., and Kingwell B. A.. 2014. Lipidomics: potential role in risk prediction and therapeutic monitoring for diabetes and cardiovascular disease. Pharmacol. Ther. 143: 12–23.
- Meikle P. J., Wong G., Tsorotes D., Barlow C. K., Weir J. M., Christopher M. J., MacIntosh G. L., Goudey B., Stern L., Kowalczyk A., et al. . 2011. Plasma lipidomic analysis of stable and unstable coronary artery disease. Arterioscler. Thromb. Vasc. Biol. 31: 2723–2732.
- Chapman M. J., Orsoni A., Robillard P., Hounslow N., Sponseller C. A., and Giral P.. 2014. Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies. Curr. Med. Res. Opin. 30: 775–784.
- Kontush A., Chantepie S., and Chapman M. J.. 2003. Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress. Arterioscler. Thromb. Vasc. Biol. 23: 1881–1888.
- Zerrad-Saadi A., Therond P., Chantepie S., Couturier M., Rye K. A., Chapman M. J., and Kontush A.. 2009. HDL3-mediated inactivation of LDL-associated phospholipid hydroperoxides is determined by the redox status of apolipoprotein A-I and HDL particle surface lipid rigidity: relevance to inflammation and atherogenesis. Arterioscler. Thromb. Vasc. Biol. 29: 2169–2175.
- Weir J. M., Wong G., Barlow C. K., Greeve M. A., Kowalczyk A., Almasy L., Comuzzie A. G., Mahaney M. C., Jowett J. B., Shaw J., et al. . 2013. Plasma lipid profiling in a large population-based cohort. J. Lipid Res. 54: 2898–2908.
- Dunstan D. W., Zimmet P. Z., Welborn T. A., Cameron A. J., Shaw J., de Courten M., Jolley D., and McCarty D. J.. 2002. The Australian Diabetes, Obesity and Lifestyle study (AusDiab)–methods and response rates. Diabetes Res. Clin. Pract. 57: 119–129.
- Mitchell B. D., Kammerer C. M., Blangero J., Mahaney M. C., Rainwater D. L., Dyke B., Hixson J. E., Henkel R. D., Sharp R. M., Comuzzie A. G., et al. . 1996. Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study. Circulation. 94: 2159–2170.
- Hansel B., Giral P., Nobecourt E., Chantepie S., Bruckert E., Chapman M. J., and Kontush A.. 2004. Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity. J. Clin. Endocrinol. Metab. 89: 4963–4971.
- Gayoso-Diz P., Otero-Gonzalez A., Rodriguez-Alvarez M. X., Gude F., Garcia F., De Francisco A., and Quintela A. G.. 2013. Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age: EPIRCE cross-sectional study. BMC Endocr. Disord. 13: 47.
- Barter P. J., Brandrup-Wognsen G., Palmer M. K., and Nicholls S. J.. 2010. Effect of statins on HDL-C: a complex process unrelated to changes in LDL-C: analysis of the VOYAGER database. J. Lipid Res. 51: 1546–1553.
- Nelson J. C., Jiang X. C., Tabas I., Tall A., and Shea S.. 2006. Plasma sphingomyelin and subclinical atherosclerosis: findings from the multi-ethnic study of atherosclerosis. Am. J. Epidemiol. 163: 903–912.
- Fournier N., Paul J. L., Atger V., Cogny A., Soni T., de la Llera-Moya M., Rothblat G., and Moatti N.. 1997. HDL phospholipid content and composition as a major factor determining cholesterol efflux capacity from Fu5AH cells to human serum. Arterioscler. Thromb. Vasc. Biol. 17: 2685–2691.
- Kontush A., Therond P., Zerrad A., Couturier M., Negre-Salvayre A., de Souza J. A., Chantepie S., and Chapman M. J.. 2007. Preferential sphingosine-1-phosphate enrichment and sphingomyelin depletion are key features of small dense HDL3 particles: relevance to antiapoptotic and antioxidative activities. Arterioscler. Thromb. Vasc. Biol. 27: 1843–1849.
- Würtz P., Havulinna A. S., Soininen P., Tynkkynen T., Prieto-Merino D., Tillin T., Ghorbani A., Artati A., Wang Q., Tiainen M., et al. . 2015. Metabolite profiling and cardiovascular event risk: a prospective study of 3 population-based cohorts. Circulation. 131: 774–785.
- Demetz E., Schroll A., Auer K., Heim C., Patsch J. R., Eller P., Theurl M., Theurl I., Theurl M., Seifert M., et al. . 2014. The arachidonic acid metabolome serves as a conserved regulator of cholesterol metabolism. Cell Metab. 20: 787–798.
- Jürgens G., Fell A., Ledinski G., Chen Q., and Paltauf F.. 1995. Delay of copper-catalyzed oxidation of low density lipoprotein by in vitro enrichment with choline or ethanolamine plasmalogens. Chem. Phys. Lipids. 77: 25–31.
- Mankidy R., Ahiahonu P. W., Ma H., Jayasinghe D., Ritchie S. A., Khan M. A., Su-Myat K. K., Wood P. L., and Goodenowe D. B.. 2010. Membrane plasmalogen composition and cellular cholesterol regulation: a structure activity study. Lipids Health Dis. 9: 62.
- Marigny K., Pedrono F., Martin-Chouly C. A., Youmine H., Saiag B., and Legrand A. B.. 2002. Modulation of endothelial permeability by 1-O-alkylglycerols. Acta Physiol. Scand. 176: 263–268.
- Pynn C. J., Henderson N. G., Clark H., Koster G., Bernhard W., and Postle A. D.. 2011. Specificity and rate of human and mouse liver and plasma phosphatidylcholine synthesis analyzed in vivo. J. Lipid Res. 52: 399–407.
- Vance D. E. 2013. Physiological roles of phosphatidylethanolamine N-methyltransferase. Biochim. Biophys. Acta. 1831: 626–632.
- Reiner Z., Catapano A. L., De Backer G., Graham I., Taskinen M. R., Wiklund O., Agewall S., Alegria E., Chapman M. J., Durrington P., et al. . 2011. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur. Heart J. 32: 1769–1818.
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