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Chronic Exercise Reduces CETP and Mesterolone Treatment Counteracts Exercise Benefits on Plasma Lipoproteins Profile: Studies in Transgenic Mice

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Lipids

Abstract

Regular exercise and anabolic androgenic steroids have opposing effects on the plasma lipoprotein profile and risk of cardio-metabolic diseases in humans. Studies in humans and animal models show conflicting results. Here, we used a mice model genetically modified to mimic human lipoprotein profile and metabolism. They under-express the endogenous LDL receptor gene (R1) and express a human transgene encoding the cholesteryl ester transfer protein (CETP), normally absent in mice. The present study was designed to evaluate the independent and interactive effects of testosterone supplementation, exercise training and CETP expression on the plasma lipoprotein profile and CETP activity. CETP/R1 and R1 mice were submitted to a 6-week swimming training and mesterolone (MEST) supplementation in the last 3 weeks. MEST treatment increased markedly LDL levels (40%) in sedentary CETP/R1 mice and reduced HDL levels in exercised R1 mice (18%). A multifactorial ANOVA revealed the independent effects of each factor, as follows. CETP expression reduced HDL (21%) and increased non-HDL (15%) fractions. MEST treatment increased the VLDL concentrations (42%) regardless of other interventions. Exercise training reduced triacylglycerol (25%) and free fatty acids (20%), increased both LDL and HDL (25–33%), and reduced CETP (19%) plasma levels. Significant factor interactions showed that the increase in HDL induced by exercise is explained by reducing CETP activity and that MEST blunted the exercise-induced elevation of HDL-cholesterol. These results reinforce the positive metabolic effects of exercise, resolved a controversy about CETP response to exercise and evidenced MEST potency to counteract specific exercise benefits.

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Abbreviations

AAS:

Anabolic androgenic steroids

ANOVA:

Analysis of variance

Apo:

Apolipoprotein

ApoB:

Apolipoprotein B

ApoE:

Apolipoprotein E

CETP:

Cholesteryl ester transfer protein

CETP/R1:

Mice over-expressing CETP and expressing only one allele of the endogenous LDL receptor gene

CHOL:

Cholesterol

CVD:

Cardiovascular diseases

FFA:

Plasma-free fatty acids

FPLC:

Fast protein liquid chromatography

HDL:

High-density lipoproteins

HL:

Hepatic lipase

LDL:

Low-density lipoprotein

LP:

Lipoproteins

LPL:

Lipoprotein lipase

MEST:

Mesterolone (1-alpha-methyl-5-alpha-androstan-17beta-ol-3-one)

R1:

Mice expressing only one allele of the endogenous LDL receptor gene

TAG:

Triacylglycerol

VLDL:

Very low-density lipoprotein

References

  1. Hartgens F, Kuipers H (2007) Effects of androgenic–anabolic steroids in athletes. Sports Med 34:513–554

    Article  Google Scholar 

  2. Turillazzi E, Perilli G, Di Paolo M, Neri M, Riezzo I, Fineschi V (2011) Side effects of AAS abuse: an overview. Mini Rev Med Chem 11:374–389

    Article  CAS  PubMed  Google Scholar 

  3. Fontana K, Oliveira HC, Leonardo MB, Mandarim-de-Lacerda CA, da Cruz-Hofling MA (2008) Adverse effect of the anabolic–androgenic steroid mesterolone on cardiac remodelling and lipoprotein profile is attenuated by aerobic exercise training. Int J Exp Pathol 89:358–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Soe KL, Soe M, Gluud C (1992) Liver pathology associated with the use of anabolic–androgenic steroids. Liver 12:73–79

    Article  CAS  PubMed  Google Scholar 

  5. Fontana K, Aldrovani M, de Paoli F, Oliveira HC, de Campos Vidal B, da Cruz-Hofling MA (2008) Hepatocyte nuclear phenotype: the cross-talk between anabolic androgenic steroids and exercise in transgenic mice. Histol Histopathol 23:1367–1377

    CAS  PubMed  Google Scholar 

  6. Thompson P (2003) Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease. Arterioscler Thromb Vasc Biol 23:1319–1321

    Article  CAS  PubMed  Google Scholar 

  7. Enkhmaa B, Surampudi P, Anuurad E, Berglund L (2015) Lifestyle changes: effect of diet, exercise, functional food, and obesity treatment, on lipids and lipoproteins. In: De Groot LJ et al (eds) Source endotext [Internet]. MDText.com, Inc., South Dartmouth, pp 2000–2015

    Google Scholar 

  8. Tall AR (2002) Exercise to reduce cardiovascular risk—how much is enough? N Engl J Med 347:1522–1524

    Article  PubMed  Google Scholar 

  9. Hagberg JM (1985) Do genetic variations alter the effects of exercise training on cardiovascular disease and can we identify the candidate variants now or in the future? J Appl Physiol 111:916–928

    Article  Google Scholar 

  10. Roth SM, Rankinen T, Hagberg JM, Loos RJ, Perusse L, Sarzynski MA, Wolfarth B, Bouchard C (2012) Advances in exercise, fitness, and performance genomics in 2011. Med Sci Sports Exerc 44:809–817

    Article  PubMed  PubMed Central  Google Scholar 

  11. Oliveira HC, de Faria EC (2011) Cholesteryl ester transfer protein: the controversial relation to atherosclerosis and emerging new biological roles. IUBMB Life 63:248–257

    Article  CAS  PubMed  Google Scholar 

  12. Barter PJ, Rye KA (2012) Cholesteryl ester transfer protein inhibition as a strategy to reduce cardiovascular risk. J Lipid Res 53:1755–1766

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ha YC, Barter PJ (1982) Differences in plasma cholesteryl ester transfer activity in sixteen vertebrate species. Comp Biochem Physiol B 71:265–269

    Article  CAS  PubMed  Google Scholar 

  14. Cazita PM, Berti JA, Aoki C, Gidlund M, Harada LM, Nunes VS, Quintao EC, Oliveira HC (2003) Cholesteryl ester transfer protein expression attenuates atherosclerosis in ovariectomized mice. J Lipid Res 44:33–40

    Article  CAS  PubMed  Google Scholar 

  15. Casquero ACBJ, Salerno AG, Bighetti EJ, Cazita PM, Ketelhuth DF, Gidlund M, Oliveira HC (2006) Atherosclerosis is enhanced by testosterone deficiency and attenuated by CETP expression in transgenic mice. J Lipid Res 47:1526–1534

    Article  CAS  PubMed  Google Scholar 

  16. Gupta AK, Ross EA, Myers JN, Kashyap ML (1993) Increased reverse cholesterol transport in athletes. Metabolism 42:684–690

    Article  CAS  PubMed  Google Scholar 

  17. Seip RL, Moulin P, Cocke T, Tall A, Kohrt WM, Mankowitz K, Semenkovich CF, Ostlund R, Schonfeld G (1993) Exercise training decreases plasma cholesteryl ester transfer protein. Arterioscler Thromb 13:1359–1367

    Article  CAS  PubMed  Google Scholar 

  18. Vislocky LM, Pikosky MA, Rubin KH, Vega-Lopez S, Gaine PC, Martin WF, Zern TL, Lofgren IE, Fernandez ML, Rodriguez NR (2009) Habitual consumption of eggs does not alter the beneficial effects of endurance training on plasma lipids and lipoprotein metabolism in untrained men and women. J Nutr Biochem 20:26–34

    Article  CAS  PubMed  Google Scholar 

  19. Rocco DD, Okuda LS, Pinto RS, Ferreira FD, Kubo SK, Nakandakare ER, Quintao EC, Catanozi S, Passarelli M (2011) Aerobic exercise improves reverse cholesterol transport in cholesteryl ester transfer protein transgenic mice. Lipids 46:617–625

    Article  CAS  PubMed  Google Scholar 

  20. Wilund K, Ferrell RE, Phares DA, Goldberg AP, Hagberg JM (2002) Changes in high-density lipoprotein-cholesterol subfractions with exercise training may be dependent on cholesteryl ester transfer protein (CETP) genotype. Metabolism 51:774–778

    Article  CAS  PubMed  Google Scholar 

  21. Jiang XC, Agellon LB, Walsh A, Breslow JL, Tall A (1992) Dietary cholesterol increases transcription of the human cholesteryl ester transfer protein gene in transgenic mice. Dependence on natural flanking sequences. J Clin Invest 90:1290–1295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Berti JA, Amaral ME, Boschero AC, Nunes VS, Harada LM, Castilho LN, Oliveira HC (2001) Thyroid hormone increases plasma cholesteryl ester transfer protein activity and plasma high-density lipoprotein removal rate in transgenic mice. Metabolism 50:530–536

    Article  CAS  PubMed  Google Scholar 

  23. Evangelista FS, Brum PC, Krieger JE (2003) Duration-controlled swimming exercise training induces cardiac hypertrophy in mice. Braz J Med Biol Res 36:1751–1759

    Article  CAS  PubMed  Google Scholar 

  24. Oliveira HC, Quintao EC (1996) ‘In vitro’ cholesteryl ester bidirectional flow between high-density lipoproteins and triglyceride-rich emulsions: effects of particle concentration and composition, cholesteryl ester transfer activity and oleic acid. J Biochem Biophys Methods 32:45–57

    Article  CAS  PubMed  Google Scholar 

  25. Ehnholm C, Kuusi T (1986) Preparation, characterization, and measurement of hepatic lipase. Methods Enzymol 129:716–738

    Article  CAS  PubMed  Google Scholar 

  26. Futema M, Kumari M, Boustred C, Kivimaki M, Humphries SE (2015) Would raising the total cholesterol diagnostic cut-off from 7.5 to 9.3 mmol/l improve detection rate of patients with monogenic familial hypercholesterolaemia? Atherosclerosis 239:295–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zmuda JM, Fahrenbach MC, Younkin BT, Bausserman LL, Terry RB, Catlin DH, Thompson PD (1993) The effect of testosterone aromatization on high-density lipoprotein cholesterol level and postheparin lipolytic activity. Metabolism 42:446–450

    Article  CAS  PubMed  Google Scholar 

  28. Sader MA, Griffiths KA, McCredie RJ, Handelsman DJ, Celermajer DS (2001) Androgenic anabolic steroids and arterial structure and function in male bodybuilders. J Am Coll Cardiol 37:224–230

    Article  CAS  PubMed  Google Scholar 

  29. Gordon B, Chen S, Durstine JL (2014) The effects of exercise training on the traditional lipid profile and beyond. Curr Sports Med Rep 13:253–259

    Article  PubMed  Google Scholar 

  30. Foger B, Chase M, Amar MJ, Vaisman BL, Shamburek RD, Paigen B, Fruchart-Najib J, Paiz JA, Koch CA, Hoyt RF, Brewer HB Jr, Santamarina-Fojo S (1999) Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J Biol Chem 274:36912–36920

    Article  CAS  PubMed  Google Scholar 

  31. Herd SL, Kiens B, Boobis LH, Hardman AE (2001) Moderate exercise, postprandial lipemia, and skeletal muscle lipoprotein lipase activity. Metabolism 50:756–762

    Article  CAS  PubMed  Google Scholar 

  32. Katzmarzyk PT, Leon AS, Rankinen T, Gagnon J, Skinner JS, Wilmore JH, Rao DC, Bouchard C (2001) Changes in blood lipids consequent to aerobic exercise training related to changes in body fatness and aerobic fitness. Metabolism 50:841–848

    Article  CAS  PubMed  Google Scholar 

  33. Magkos F (2009) Basal very low-density lipoprotein metabolism in response to exercise: mechanisms of hypotriacylglycerolemia. Prog Lipid Res 48:171–190

    Article  CAS  PubMed  Google Scholar 

  34. Kersten S (2014) Physiological regulation of lipoprotein lipase. Biochim Biophys Acta 1841:919–933

    Article  CAS  PubMed  Google Scholar 

  35. Greger NG, Insull W Jr, Probstfield JL, Keenan BS (1990) High-density lipoprotein response to 5-alpha-dihydrotestosterone and testosterone in Macaca fascicularis: a hormone-responsive primate model for the study of atherosclerosis. Metabolism 39:919–924

    Article  CAS  PubMed  Google Scholar 

  36. Larsen BA, Nordestgaard BG, Stender S, Kjeldsen K (1993) Effect of testosterone on atherogenesis in cholesterol-fed rabbits with similar plasma cholesterol levels. Atherosclerosis 99:79–86

    Article  CAS  PubMed  Google Scholar 

  37. Bruck B, Brehme U, Gugel N, Hanke S, Finking G, Lutz C, Benda N, Schmahl FW, Haasis R, Hanke H (1997) Gender-specific differences in the effects of testosterone and estrogen on the development of atherosclerosis in rabbits. Arterioscler Thromb Vasc Biol 17:2192–2199

    Article  CAS  PubMed  Google Scholar 

  38. Nielsen S, Karpe F (2012) Determinants of VLDL-triglycerides production. Curr Opin Lipidol 23:321–326

    Article  CAS  PubMed  Google Scholar 

  39. Høst C, Gormsen LC, Christensen B, Jessen N, Hougaard DM, Christiansen JS, Pedersen SB, Jensen MD, Nielsen S, Gravholt CH (2013) Independent effects of testosterone on lipid oxidation and VLDL-TG production: a randomized, double-blind, placebo-controlled, crossover study. Diabetes 62:1409–1416

    Article  PubMed  PubMed Central  Google Scholar 

  40. von Duvillard SP, Foxall TL, Davis WP, Terpstra AH (2000) Effects of exercise on plasma high-density lipoprotein cholesteryl ester metabolism in male and female miniature swine. Metabolism 49:826–832

    Article  Google Scholar 

  41. Frajacomo FT, Demarzo MM, Fernandes CR, Martinello F, Bachur JA, Uyemura SA, Perez SE, Garcia SB (2012) The effects of high-intensity resistance exercise on the blood lipid profile and liver function in hypercholesterolemic hamsters. Appl Physiol Nutr Metab 37:448–454

    Article  CAS  PubMed  Google Scholar 

  42. Meilhac O, Ramachandran S, Chiang K, Santanam N, Parthasarathy S (2001) Role of arterial wall antioxidant defense in beneficial effects of exercise on atherosclerosis in mice. Arterioscler Thromb Vasc Biol 21:1681–1688

    Article  CAS  PubMed  Google Scholar 

  43. Wen S, Jadhav KS, Williamson DL, Rideout TC (2013) Treadmill exercise training modulates hepatic cholesterol metabolism and circulating PCSK9 concentration in high-fat-fed mice. J Lipids 2013:908048

    Article  PubMed  PubMed Central  Google Scholar 

  44. Niebauer J, Maxwell AJ, Lin PS, Tsao PS, Kosek J, Bernstein D, Cooke JP (1999) Impaired aerobic capacity in hypercholesterolemic mice: partial reversal by exercise training. Am J Physiol 276:H1346–H1354

    CAS  PubMed  Google Scholar 

  45. Oettel M (2003) Testosterone metabolism, dose-response relationships and receptor polymorphisms: selected pharmacological/toxicological considerations on benefits versus risks of testosterone therapy in men. Aging Male 6:230–256

    Article  CAS  PubMed  Google Scholar 

  46. Urhausen A, Torsten A, Wilfried K (2003) Reversibility of the effects on blood cells, lipids, liver function and hormones in former anabolic–androgenic steroid abusers. J Steroid Biochem Mol Biol 84:369–375

    Article  CAS  PubMed  Google Scholar 

  47. McKillop G, Ballantyne D (1987) Lipoprotein analysis in bodybuilders. Int J Cardiol 17:281–288

    Article  CAS  PubMed  Google Scholar 

  48. Foger B, Wohlfarter T, Ritsch A, Lechleitner M, Miller CH, Dienstl A, Patsch JR (1994) Kinetics of lipids, apolipoproteins, and cholesteryl ester transfer protein in plasma after a bicycle marathon. Metabolism 43:633–639

    Article  CAS  PubMed  Google Scholar 

  49. Carrilho AJ, Cunha-Neto MB, Nunes VS, Lottenberg AM, Medina WL, Nakandakare ER, Musolino NR, Bronstein MD, Quintão EC (2001) Plasma cholesteryl ester transfer protein and lipoprotein levels during treatment of growth hormone-deficient adult humans. Lipids 36(6):549–554

    Article  CAS  PubMed  Google Scholar 

  50. Raposo HF, Patrício PR, Simões MC, Oliveira HC (2014) Fibrates and fish oil, but not corn oil, up-regulate the expression of the cholesteryl ester transfer protein (CETP) gene. J Nutr Biochem 25(6):669–674

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP Grant #2011/50400-0) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq #310546/2014-1). We are grateful to Adriano Affonso Mariscal and Lescio Domingos Teixeira for technical assistance.

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Author notes

  1. Andrea Camargo Casquero

    Present address: Centro Universitário de Araraquara, Araraquara, SP, 14801-340, Brazil

  2. Jairo Augusto Berti

    Present address: Universidade Estadual de Maringá, Departamento de Ciências Morfofisiológicas, Maringá, PR, 87020-900, Brazil

Authors and Affiliations

  1. Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, SP, 13083-862, Brazil

    Andrea Camargo Casquero, Jairo Augusto Berti, Laura Lauand Sampaio Teixeira & Helena Coutinho Franco de Oliveira

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  1. Andrea Camargo Casquero
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  2. Jairo Augusto Berti
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  4. Helena Coutinho Franco de Oliveira
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Contributions

ACC, JAB and LLST performed all experiments and analyzed data. ACC, JAB and HCFO conceived the study and wrote the manuscript. All authors revised and approved the final version of the manuscript.

Corresponding author

Correspondence to Helena Coutinho Franco de Oliveira.

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Casquero, A.C., Berti, J.A., Teixeira, L.L.S. et al. Chronic Exercise Reduces CETP and Mesterolone Treatment Counteracts Exercise Benefits on Plasma Lipoproteins Profile: Studies in Transgenic Mice. Lipids 52, 981–990 (2017). https://doi.org/10.1007/s11745-017-4299-1

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