Molecular mechanisms underlying the effects of cyclosporin A and sirolimus on glucose and lipid metabolism in liver, skeletal muscle and adipose tissue in an in vivo rat model

Biochemical Pharmacology

Volumn 88, Issue 2, 2014, Pages 216-228

  Fuhrmann, A ^a   Lopes, Pc ^a   Sereno, J ^b   Pedro, J ^a   Espinoza, D O ^a   Pereira, M J ^a,c   Reis, F ^b   Eriksson, J W ^c   Carvalho, E ^a,d  

^a UNIVERSITY OF COIMBRA   (Portugal)

^b UNIVERSITY OF COIMBRA   (Portugal)

^c UPPSALA UNIVERSITY   (Sweden)

^d The Portuguese Diabetes Association (APDP)   (Portugal)

Author keywords

Cyclosporin A; Diabetes; Dyslipidemia; Insulin resistance; Lipogenesis; Sirolimus

Indexed keywords

ACETYL COENZYME A CARBOXYLASE; ADIPONECTIN; CARBOHYDRATE RESPONSE ELEMENT BINDING PROTEIN; CHOLESTEROL; CYCLOSPORIN A; DIACYLGLYCEROL ACYLTRASFERASE 1; FORKHEAD BOX O1; GLUCOSE; GLUCOSE TRANSPORTER 1; GLUCOSE TRANSPORTER 2; GLUCOSE TRANSPORTER 4; INSULIN; INSULIN RECEPTOR SUBSTRATE 1; INTERLEUKIN 6; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA; RAPAMYCIN; STEROL REGULATORY ELEMENT BINDING PROTEIN 1; TRANSCRIPTION FACTOR; TRIACYLGLYCEROL; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

ADIPOCYTE; ADIPOSE TISSUE; ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; CHOLESTEROL BLOOD LEVEL; COMPARATIVE STUDY; CONTROLLED STUDY; DIABETES MELLITUS; DYSLIPIDEMIA; FATTY ACID OXIDATION; GENE EXPRESSION; GLUCONEOGENESIS; GLUCOSE BLOOD LEVEL; GLUCOSE INTOLERANCE; GLUCOSE METABOLISM; GLUCOSE TOLERANCE TEST; GLUCOSE TRANSPORT; GROWTH CURVE; IMMUNOSUPPRESSIVE TREATMENT; IN VIVO STUDY; INSULIN BLOOD LEVEL; INSULIN RESISTANCE; LIPID METABOLISM; LIPOGENESIS; LIVER; MALE; NEW ONSET DIABETES AFTER TRANSPLANTATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION; RAT; REAL TIME POLYMERASE CHAIN REACTION; REVERSE TRANSCRIPTION POLYMERASE CHAIN REACTION; SKELETAL MUSCLE; WESTERN BLOTTING; WISTAR RAT;

CYCLOSPORIN A; DIABETES; DYSLIPIDEMIA; INSULIN RESISTANCE; LIPOGENESIS; SIROLIMUS;

ADIPOSE TISSUE; ANIMALS; CYCLOSPORINE; GLUCOSE; IMMUNOSUPPRESSIVE AGENTS; LIPID METABOLISM; MALE; MUSCLE, SKELETAL; RATS; RATS, WISTAR; SIROLIMUS;

EID: 84895553061     PISSN: 00062952     EISSN: 18732968     Source Type: Journal    
DOI: 10.1016/j.bcp.2014.01.020     Document Type: Article

References (57)

1. J.M. Smith, T.L. Nemeth, and R.A. McDonald Current immunosuppressive agents: efficacy, side effects, and utilization Pediatr Clin North Am 50 2003 1283 1300
2. K.A. Bodziak, and D.E. Hricik New-onset diabetes mellitus after solid organ transplantation Traspl Int 22 2009 519 530
3. A.R. Gosmanov, and S. Dagogo-Jack Predicting, managing and preventing new-onset diabetes after transplantation Minerva Endocrinol 37 2012 233 246
4. D.N. Perrea, K.G. Moulakakis, M.V. Poulakou, I.S. Vlachos, N. Nikiteas, and A. Kostakis Correlation between lipid abnormalities and immunosuppressive therapy in renal transplant recipients with stable renal function Int Urol Nephrol 40 2008 521 527
5. S. Badiou, J.P. Cristol, and G. Mourad Dyslipidemia following kidney transplantation: diagnosis and treatment Curr Diab Rep 9 2009 305 311
6. P.J. Morris Cyclosporin A Transplantation 32 1981 349 354
7. D. Faulds, K.L. Goa, and P. Benfield Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders Drugs 45 1993 953 1040
8. D.A. Fruman, C.B. Klee, B.E. Bierer, and S.J. Burakoff Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A Proc Natl Acad Sci U S A 89 1992 3686 3690
9. F.M. Egidi Management of hyperglycaemia after pancreas transplantation: are new immunosuppressants the answer? Drugs 65 2005 153 166
10. M. Laplante, and D.M. Sabatini mTOR signaling at a glance J Cell Sci 122 2011 3589 3594
11. J.T. Cunningham, J.T. Rodgers, D.H. Arlow, F. Vazquez, V.K. Mootha, and P. Puigserver mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex Nature 450 2007 736 740
12. G.A. Soliman The integral role of mTOR in lipid metabolism Cell Cycle 10 2011 861 862
13. S.N. Sehgal Rapamune (RAPA, rapamycin, sirolimus): mechanism of action immunosuppressive effect results from blockade of signal transduction and inhibition of cell cycle progression Clin Biochem 31 1998 335 340
14. M. Naesens, D.R. Kuypers, and M. Sarwal Calcineurin inhibitor nephrotoxicity Clin J Am Soc Nephrol 4 2009 481 508
15. K.L. Ma, X.Z. Ruan, S.H. Powis, Y. Chen, J.F. Moorhead, and Z. Varghese Sirolimus modifies cholesterol homeostasis in hepatic cells: a potential molecular mechanism for sirolimus-associated dyslipidemia Transplantation 84 2007 1029 1036
16. K.M. Chow, and P.K. Li Review article: new-onset diabetes after transplantation Nephrology (Carlton) 13 2008 737 744 Review
17. O. Pankewycz, N. Leca, R. Kohli, E. Weber-Shrikant, M. Said, and M. Alnimri et al. Conversion to low-dose tacrolimus or rapamycin 3 months after kidney transplantation: a prospective, protocol biopsy-guided study Transplant Proc 43 2011 519 523
18. E. Carvalho, C. Rondinone, and U. Smith Insulin resistance in fat cells from obese Zucker rats - evidence for an impaired activation and translocation of protein kinase B and glucose transporter 4 Mol Cell Biochem 206 2000 7 16
19. G.R. Chang, Y.Y. Wu, Y.S. Chiu, W.Y. Chen, J.W. Liao, and H.M. Hsu et al. Long-term administration of rapamycin reduces adiposity, but impairs glucose tolerance in high-fat diet-fed KK/HlJ mice Basic Clin Pharmacol Toxicol 105 2009 188 198
20. N. Deblon, L. Bourgoin, C. Veyrat-Durebex, M. Peyrou, M. Vinciguerra, and A. Caillon et al. Chronic mTOR inhibition by rapamycin induces muscle insulin resistance despite weight loss in rats Br J Pharmacol 165 2012 2325 2340
21. D.D. Sarbassov, S.M. Ali, and D.M. Sabatini Growing roles for the mTOR pathway Curr Opin Cell Biol 17 2005 596 603
22. E. Oetjen, D. Baun, S. Beimesche, D. Krause, I. Cierny, and R. Blume et al. Inhibition of human insulin gene transcription by the immunosuppressive drugs cyclosporin A and tacrolimus in primary, mature islets of transgenic mice Mol Pharmacol 63 2003 1289 1295
23. L.A. zbay, K. Smidt, D.M. Mortensen, J. Carstens, K.A. Jørgensen, and J. Rungby Cyclosporin and tacrolimus impair insulin secretion and transcriptional regulation in INS-1E beta-cells Br J Pharmacol 62 2011 136 146
24. P. Gillard, E. Vandemeulebroucke, B. Keymeulen, J. Pirenne, B. Maes, and P. De Pauw et al. Functional beta-cell mass and insulin sensitivity is decreased in insulin-independent pancreas-kidney recipients Transplantation 87 2009 402 407
25. V.P. Houde, S. Brûlé, W.T. Festuccia, P.G. Blanchard, K. Bellmann, and Y. Deshaies et al. Chronic rapamycin treatment causes glucose intolerance and hyperlipidemia by upregulating hepatic gluconeogenesis and impairing lipid deposition in adipose tissue Diabetes 59 2010 1338 1348
26. G.A. Spinelli, C.R. Felipe, S.I. Park, E.L. Mandia-Sampaio, H. Tedesco-Silva Jr., and J.O. Medina-Pestana Lipid profile changes during the first year after kidney transplantation: risk factors and influence of the immunosuppressive drug regimen Transplant Proc 43 2011 3730 3737
27. P. Chakrabarti, T. English, J. Shi, C.M. Smas, and K.V. Kandror Mammalian target of rapamycin complex 1 suppresses lipolysis, stimulates lipogenesis, and promotes fat storage Diabetes 59 2010 775 781
28. A. Kumar, J.C. Lawrence Jr., D.Y. Jung, H.J. Ko, S.R. Keller, and J.K. Kim et al. Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism Diabetes 59 2010 1397 1406
29. J. Wu, Y.H. Zhu, and S.B. Patel Cyclosporin-induced dyslipoproteinemia is associated with selective activation of SREBP-2 Am J Physiol 277 1999 E1087 E1094
30. A. Asberg, K. Midtvedt, M.H. Voytovich, P.D. Line, J. Narverud, and A.V. Reisaeter et al. Calcineurin inhibitor effects on glucose metabolism and endothelial function following renal transplantation Clin Transplant 23 2009 511 518
31. M. Ikeuchi, K. Kida, Y. Goto, Y. Kaino, and H. Matsuda In vivo and in vitro effects of cyclosporin A on glucose transport by soleus muscles of mice Biochem Pharmacol 43 1992 1459 1463
32. L.A. ∅zbay, N. Møller, C. Juhl, M. Bjerre, J. Carstens, and J. Rungby et al. Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers Br J Clin Pharmacol 73 2012 536 545
33. M.J. Pereira, J. Palming, M. Rizell, M. Aureliano, E. Carvalho, and M.K. Svensson et al. mTOR inhibition with rapamycin causes impaired insulin signaling and glucose uptake in human subcutaneous and omental adipocytes Mol Cell Endocrinol 355 2012 96 105
34. F. Renström, J. Burén, and J.W. Eriksson Insulin receptor substrates-1 and -2 are both depleted but via different mechanisms after down-regulation of glucose transport in rat adipocytes Endocrinology 146 2005 3044 3051
35. E. Carvalho, P.A. Jansson, M. Axelsen, J.W. Eriksson, X. Huang, and L. Groop et al. Low cellular IRS-1 gene and protein expression predict insulin resistance and NIDDM FASEB J 13 1999 2173 2178
36. E. Carvalho, P.A. Jansson, I. Nagaev, A.M. Wenthzel, and U. Smith Defficient IRS-1 and Glut4 protein expression in adipocytes from insulin resistant subjects FASEB J 15 2001 1101 1103
37. E. Carvalho, B. Eliasson, C. Wesslau, and U. Smith Impaired phosphorylation and insulin-stimulated translocation to the plasma membrane of Protein Kinase B/Akt in adipocytes from type 2 diabetic subjects Diabetologia 43 2000 1107 1115
38. EASD 2012, Berlin, Germany: Poster Presentation M.J. Pereira, J. Palming, M. Svensson, M. Aureliano, E. Carvalho, and J.W. Eriksson Cyclosporin A and tacrolimus can reduce GLUT4 at the cell surface via increased endocytosis and this leads to impaired cellular glucose uptake Diabetologia 55 Suppl. 1 2012 S229 S549
39. Pereira MJ, Palming J, Rizell M, Aureliano M, Carvalho E, Svensson MK, et al. Cyclosporine A and tacrolimus reduce cell-surface amount of GLUT4 via increased endocytosis: a potential mechanism for the diabetogenic effects of immunosuppressive agents. Unpublished results.
40. I.S. Wood, and P. Trayhurn Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins Br J Nutr 89 2003 3 9
41. J.P. Bastard, M. Maachi, C. Lagathu, M.J. Kim, M. Caron, and H. Vidal et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance Eur Cytokine Netw 17 2006 4 12
42. M.J. Pereira, J. Palming, M. Rizell, M. Aureliano, E. Carvalho, and M.K. Svensson et al. The immunosuppressive agents rapamycin, cyclosporin A and tacrolimus increase lipolysis, inhibit lipid storage and alter expression of genes involved in lipid metabolism in human adipocytes Mol Cell Endocrinol 365 2013 260 269
43. M. Rydén, E. Arvidsson, L. Blomqvist, L. Perbeck, A. Dicker, and P. Arner Targets for TNF-alpha-induced lipolysis in human adipocytes Biochem Biophys Res Commun 318 2004 168 175
44. V. Schaeffer, S. Arbabi, I.A. Garcia, M.L. Knoll, J. Cuschieri, and E.M. Bulger et al. Role of the mTOR pathway in LPS-activated monocytes: influence of hypertonic saline J Surg Res 171 2011 769 776
45. Z. Wedellov, J. Dietrich, M. Siklová-Vítková, K. Kološtová, M. Kováčiková, and M. Dušková et al. Adiponectin inhibits spontaneous and catecholamine-induced lipolysis in human adipocytes of non-obese subjects through AMPK-dependent mechanisms Physiol Res 60 2011 139 148
46. H. Liang, and W.F. Ward PGC-1alpha: a key regulator of energy metabolism Adv Physiol Educ 30 2006 145 151
47. T. Kitamura, Y.I. Kitamura, Y. Funahashi, C.J. Shawber, D.H. Castrillon, and R. Kollipara et al. A Foxo/Notch pathway controls myogenic differentiation and fiber type specification J Clin Invest 117 2007 2477 2485
48. R.J. Southgate, B. Neill, O. Prelovsek, A. El-Osta, Y. Kamei, and S. Miura et al. FOXO1 regulates the expression of 4E-BP1 and inhibits mTOR signaling in mammalian skeletal muscle J Biol Chem 282 2007 21176 21186
49. D.L. Allen, and T.G. Unterman Regulation of myostatin expression and myoblast differentiation by FoxO and SMAD transcription factors Am J Physiol Cell Physiol 292 2007 C188 C199
50. J. Nakae, T. Kitamura, Y. Kitamura, W.H. Biggs 3rd, K.C. Arden, and D. Accili The forkhead transcription factor Foxo1 regulates adipocyte differentiation Dev Cell 4 2003 119 129
51. M. Matsumoto, S. Han, T. Kitamura, and D. Accili Dual role of transcription factor FoxO1 in controlling hepatic insulin sensitivity and lipid metabolism J Clin Invest 116 2006 2464 2472
52. M. Foretz, C. Pacot, I. Dugail, P. Lemarchand, C. Guichard, and X. Le Lièpvre et al. ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose Mol Cell Biol 19 1999 3760 3768
53. K. Iizuka, and Y. Horikawa ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome Endocrinology 55 2008 617 624
54. N.B. Ruderman, A.K. Saha, and E.W. Kraegen Minireview: malonyl CoA, AMP-activated protein kinase, and adiposity Endocrinology 144 2003 5166 5171
55. J. Cao, Y. Zhou, H. Peng, X. Huang, S. Stahler, and V. Suri et al. Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases J Biol Chem 286 2011 41838 41851
56. J.D. McGarry Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes Diabetes 51 2002 7 18
57. M. Roden, T.B. Price, G. Perseghin, K.F. Petersen, D.L. Rothman, and G.W. Cline et al. Mechanism of free fatty acid-induced insulin resistance in humans J Clin Invest 97 1996 2859 2865