Carnitine in metabolic disease: Potential for pharmacological intervention

Pharmacology and Therapeutics

Volumn 120, Issue 2, 2008, Pages 149-156

  Arduini, Arduino ^a   Bonomini, Mario ^b   Savica, Vincenzo ^c   Amato, Antonino ^d   Zammit, Victor ^e  

^a R and D Department   (Italy)

^b University Hospital of Chieti   (Italy)

^c UNIVERSITY OF MESSINA   (Italy)

^d Sigma Tau SpA   (Italy)

^e UNIVERSITY OF WARWICK   (United Kingdom)

Author keywords

Diabetes; Dyslipidemia; Hemodialysis; Insulin resistance; l carnitine; Metabolism; Peritoneal dialysis; Uremia

Indexed keywords

CARNITINE;

CARNITINE DEFICIENCY; CLINICAL TRIAL; DISEASE MODEL; DRUG EFFECT; DRUG EXCRETION; DRUG MECHANISM; DRUG RESPONSE; DYSLIPIDEMIA; HEMODIALYSIS PATIENT; HUMAN; INSULIN RESISTANCE; KIDNEY FAILURE; METABOLIC DISORDER; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PRIORITY JOURNAL; REVIEW;

ANIMALS; CARNITINE; CLINICAL TRIALS AS TOPIC; HUMANS; KIDNEY FAILURE, CHRONIC; METABOLIC DISEASES; RENAL DIALYSIS; TISSUE DISTRIBUTION;

EID: 53749084068     PISSN: 01637258     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2008.08.008     Document Type: Review

References (79)

1. Abdel-aleem S., Sayed-Ahmed M., Nada M.A., Hendrickson S.C., St Louis J., and Lowe J.E. Stimulation of non-oxidative glucose utilization by l-carnitine in isolated myocytes. J Mol Cell Cardiol 27 (1995) 2465-2472
2. Ahmad S. l-carnitine in dialysis patients. Semin Dial 14 (2001) 209-217
3. Al-Shurbaji A., Berglund L., Berge R.K., Cederblad G., and Humble E. On the relationship between hepatic carnitine, fatty acid oxidation and triglyceride biosynthesis in nephrosis. Lipids 32 (1997) 847-852
4. Arduini A., Gorbunov N., Arrigoni-Martelli A., et al. Effects of l-carnitine and its acetate and propionate esters on the molecular dynamics of human erythrocyte membrane. Biochim Biophys Acta 1146 (1993) 229-235
5. Bahl J., Navin T., Manian A.A., and Bressler R. Carnitine transport in isolated adult rat heart myocytes and the effect of 7,8-diOH chlorpromazine. Circ Res 48 (1981) 378-385
6. Biolo G., Stulle M., Bianco F., Mengozzi G., Barazzoni R., Vasile A., et al. Insulin action on glucose and protein metabolism during l-carnitine supplementation in maintenance haemodialysis patients. Nephrol Dial Transplant 23 (2008) 991-997
7. Bohmer T., Eiklid K., and Jonsen J. Carnitine uptake into human heart cells in culture. Biochim. Biophys. Acta 465 (1977) 627-633
8. Brady L.J., Knoeber C.M., Hoppel C.L., Leathers C.W., McFarland D., and Brady P.S. Pharmacologic action of l-carnitine on hypertriglyceridemia in obese Zucker rats. Metabolism 35 (1986) 555-562
9. Brass E.P., Hoppel C.L., and Hiatt W.R. Effect of intravenous l-carnitine on carnitine homeostasis and fuel metabolism during exercise in humans. Clin Pharmacol Ther 55 (1994) 681-692
10. Brass E.P., Adler S., Sietsema K.E., Hiatt W.R., Orlando A.M., and Amato A. Intravenous l-carnitine increases plasma carnitine, reduces fatigue, and may preserve exercise capacity in hemodialysis patients. Am J Kidney Dis 37 (2001) 1018-1028
11. Bremer J. Carnitine metabolism and functions. Physiol Rev 63 (1983) 1420-1480
12. Broderick T.L., Quinney H.S., and Lopaschuk G.D. Carnitine stimulation of glucose oxidation in the fatty acid perfused isolated working rat heart. J Biol Chem 267 (1992) 3758-3763
13. Broderick T.L., Baker C.C., Quinney H.S., and Lopaschuk G.D. Beneficial effect of carnitine on mechanical recovery of rat hearts perfused after a transient period of global ischemia is accompanied by a stimulation of glucose oxidation. Circulation 87 (1993) 972-981
14. Broderick T.L., Quinney H.S., and Lopaschuk G.D. l-carnitine increases glucose metabolism and mechanical function following ischaemia in diabetic rat heart. Cardiovasc Res 29 (1995) 373-378
15. Coleman R.A., and Lee D.P. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipis Res 43 (2004) 134-176
16. Dai T., Abou-Rjaily G.A., Al-Share' Q.Y., Yang Y., Fernstrom M.A., Deangelis A.M., et al. Interaction between altered insulin and lipid metabolism in CEACAM1-inactive transgenic mice. J Biol Chem 279 (2004) 45155-45161
17. Davini P., Bigalli A., Lamanna F., and Boem A. Controlled study on l-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res 18 (1992) 355-365
18. Demeyere R., Lormans P., Weidler B., Minten J., Van Aken H., and Flameng W. Cardioprotective effects of carnitine in extensive aortocoronary bypass grafting: A double-blind, randomized, placebo-controlled clinical trial. Anesth Analg 71 (1990) 520-528
19. Dyck J.R., Hopkins T.A., Bonnet S., Michelakis E.D., Young M.E., Watanabe M., et al. Absence of malonyl coenzyme A decarboxylase in mice increases cardiac glucose oxidation and protects the heart from ischemic injury. Circulation 114 (2006) 1721-1728
20. Emmison N., Zammit V.A., and Agius L. Triacylglycerol accumulation and secretion in hepatocyte cultures. Effects of insulin, albumin and Triton WR 1339. Biochem J 285 (1992) 655-660
21. Evans A.M. Dialysis-related carnitine disorder and Levocarnitine pharmacology. Am J Kidney Dis 41 (2003) S13-S26
22. Evans A.M., and Fornasini G. Pharmacokinetics of l-carnitine. Clin Pharmacokinet 42 (2003) 941-967
23. Fagher B., Cederblad G., Monti M., Olsson L., Rasmussen B., and Thysell H. Carnitine and left ventricular function in haemodialysis patients. Scand J Clin Lab Invest 45 (1985) 193-198
24. Ferrannini E., Buzzigoli G., Bevilacqua S., Boni C., Del Chiaro D., Oleggini M., et al. Interaction of carnitine with insulin-stimulated glucose metabolism in humans. Am J Physiol 255 (1988) E946-E952
25. Gokal R. Peritoneal dialysis in the 21st century: An analysis of current problems and future developments. J Am Soc Nephrol 13 (2002) S104-116
26. Grefhorst A., Hoekstra J., Derks T.G., Ouwens D.M., Baller J.F., Havinga R., Havekes L.M., Romijn J.A., and Kuipers F. Acute hepatic steatosis in mice by blocking beta-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production. Am J Physiol 289 (2005) G592-G598
27. Gunal A.I., Celiker H., Dönder E., and Günal S.Y. The effect of l-carnitine on insulin resistance in hemodialysed patients with chronic renal failure. J Nephrol 12 (1999) 38-40
28. Hurot J.M., Cucherat M., Haugh M., and Fouque D. Effects of l-carnitine supplementation in maintenance hemodialysis patients: A systematic review. J Am Soc Nephrol 13 (2002) 708-714
29. Huss J.M., and Kelly D.P. Mitochondrial energy metabolism in heart failure: A question of balance. J Clin Invest 115 (2005) 547-555
30. Iliceto S., Scrutinio D., Bruzzi P., D'Ambrosio G., Boni L., Biasco G., et al. Effects of l-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: The l-carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol 26 (1995) 380-387
31. Kazory A., and Boss E.A. Contemporary trends in the pharmacological and extracorporeal management of heart failure: A nephrologic perspective. Circulation 117 (2008) 975-983
32. Kelley D.E., and Mandarino L.J. Fuel selection in human skeletal muscle in insulin resistance: A reexamination. Diabetes 49 (2000) 677-683
33. Koves T.R., Ussher J.R., Noland R.C., Slentz D., Mosedale M., Ilkayeva O., et al. Mitochondrial overload and incomplete fatty acid oxidation contribute to skeletal muscle insulin resistance. Cell Metab 7 (2008) 45-56
34. Kwan B.C., Kronenberg F., Beddhu S., and Cheung A.K. Lipoprotein metabolism and lipid management in chronic kidney disease. J Am Soc Nephrol 18 (2007) 1246-1261
35. Liedtke J.A., and Nellis S.H. Effects of carnitine in ischemic and fatty acid supplemented swine hearts. J Clin. Invest 64 (1979) 440-447
36. Liu J., and Rosner M.H. Lipid abnormalities associated with end-stage renal disease. Semin Dial 19 (2006) 32-40
37. Lopaschuk G.D., Rebeyka I.M., and Allard M.F. Metabolic modulation: A means to mend a broken heart. Circulation 105 (2002) 140-142
38. Löster H., Miehe K., Punzel M., Stiller O., Pankau H., and Schauer J. Prolonged oral l-carnitine substitution increases bicycle ergometer performance in patients with severe, ischemically induced cardiac insufficiency. Cardiovasc Drugs Ther 13 (1999) 537-546
39. Marsh J.B., Welty F.K., and Schaefer E.J. Stable isotope turnover of apolipoproteins of high-density lipoproteins in humans. Curr Opin Lipidol 11 (2000) 261-266
40. Mingrone G., Greco A.V., Capristo E., Benedetti G., Giancaterini A., De Gaetano A., et al. l-carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr 18 (1999) 77-82
41. Müller D.M., Seim H., Kiess W., Löster H., and Richter T. Effects of oral l-carnitine supplementation on in vivo long-chain fatty acid oxidation in healthy adults. Metabolism 51 (2002) 1389-1399
42. Ontko J.A., Cheng Q., and Yamamoto M. Metabolic factors underlying high serum triglycerides in the normal hamster. J Lipid Res 31 (1990) 1983-1992
43. Overington J.P., Al-Lazikani B., and Hopkins A.L. How many drug targets are there?. Nat Rev Drug Discov 5 (2006) 993-996
44. Petersen K.F., Dufour S., Befroy D., Lehrke M., Hendler R.E., and Shulman G.I. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54 (2005) 603-608
45. Power R.A., Hulver M.W., Zhang J.Y., Dubois J., Marchand R.M., Ilkayeva O., et al. Carnitine revisited: Potential use as adjunctive treatment in diabetes. Diabetologia 50 (2007) 824-832
46. Prichard S.S. Impact of dyslipidemia in end-stage renal disease. J Am Soc Nephrol 14 (2003) S315-S320
47. Rajasekar P., and Anuradha C.V. Fructose-induced hepatic gluconeogenesis: Effect of l-carnitine. Life Sci 80 (2007) 1176-1183
48. Ramsay R.R., and Arduini A. The carnitine acyltransferases and their role in modulating acyl-CoA pools. Arch Biochem Biophys 302 (1993) 307-314
49. Ramsay R.R., and Naismith J.H. A snapshot of carnitine acetyltransferase. Trends Biochem Sci 28 (2003) 343-346
50. Ramsay R.R., and Zammit. Carnitine acyltransferases and their influence on CoA pools in health and disease. Mol Aspects Med 25 (2004) 475-493
51. Randle P.J. Regulatory interactions between lipids and carbohydrates: The glucose fatty acid cycle after 35 years. Diabetes Metab Rev 14 (1998) 263-283
52. Rebouche C.J., and Engel A.G. Kinetic compartmental analysis of carnitine metabolism in the human carnitine deficiency syndromes. J Clin Invest 73 (1984) 857-867
53. Rebouche C. Carnitine function and requirements during the life cycle. FASEB J 6 (1992) 3379-3386
54. Rodrigues B., Xiang H., and McNeill J.H. Effects of l-carnitine treatment on lipid metabolism and cardiac performance in chronically diabetic rats. Diabetes 37 (1988) 1358-1364
55. Rodrigues B., Seccombe D., and McNeill J.H. Lack of effect of oral l-carnitine treatment on lipid metabolism and cardiac function in chronically diabetic rats. Can J Physiol Pharmacol 68 (1990) 1601-1608
56. Saddik M., Gamble J., Witters L.A., and Lopaschuk G.D. Acety-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem 268 (1993) 25836-25845
57. Schmitz-Peiffer C. Signalling aspects of insulin resistance in skeletal muscle: Mechanisms induced by lipid oversupply. Cell Signal 12 (2000) 583-594
58. Schreiber B. Common misconceptions about levocarnitine and dialysis. Semin Dial 18 (2005) 349-351
59. Stanley W.C., Lopaschuk G.D., Hall J.L., and McCormack J.G. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res 34 (1997) 25-33
60. Stanley W.C., Recchia F.A., and Lopaschuk G.D. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85 (2005) 1093-1129
61. Steiber A., Kerner J., and Hoppel C.L. Carnitine: A nutritional, biosynthetic, and functional perspective. Mol Aspects Med 25 (2004) 455-473
62. Steinman T.I. l-carnitine supplementation in dialysis patients: Does the evidence justify its use?. Semin Dial 18 (2005) 1-2
63. Stephens F.B., Constantin-Teodosiu D., Laithwaite D., Simpson E.J., and Greenhaff P.L. An acute increase in skeletal muscle carnitine content alters fuel metabolism in resting human skeletal muscle. J Clin Endocrinol Metab 91 (2006) 5013-5018
64. Stephens F.B., Constantin-Teodosiu D., and Greenhaff P.L. New insights concerning the role of carnitine in the regulation of fuel metabolism in skeletal muscle. J Physiol 581 (2007) 431-444
65. Storlien L., Oakes N.D., and Kelley D.E. Metabolic flexibility. Proc Nutr Soc 63 (2004) 363-368
66. Summers S.A. Ceramides in insulin resistance and lipotoxicity. Prog Lipid Res 45 (2006) 42-72
67. Szuromi P., Vinson V., and Marshall E. Rethinking drug discovery. Science 303 (2004) 1795
68. Tarantini G., Scrutinio D., Bruzzi P., Boni L., Rizzon P., and Iliceto S. Metabolic treatment with l-carnitine in acute anterior ST segment elevation myocardial infarction. A randomized controlled trial. Cardiology 106 (2006) 215-223
69. Tein I., Bukovac S.W., and Xie Z.W. Characterization of the human plasmalemmal carnitine transporter in cultured skin fibroblasts. Arch Biochem Biophys 329 (1996) 145-155
70. Tein I. Carnitine transport: Pathophysiology and metabolism of known molecular defects. J Inherit Metab Dis 26 (2003) 147-169
71. Treem W.R., Stanley C.A., Finegold D.N., Hale D.E., and Coates P.M. Primary carnitine deficiency due to a failure of carnitine transport in kidney, muscle, and fibroblasts. N Engl J Med 319 (1988) 1331-1336
72. Vacha G.M., Giorcelli G., Siliprandi N., and Corsi M. Favorable effects of l-carnitine treatment on hypertriglyceridemia in hemodialysis patients: Decisive role of low levels of high-density lipoprotein-cholesterol. Am J Clin Nutr 38 (1983) 532-540
73. Vacha G.M., Giorcelli G., d'Iddio S., Valentini G., Bagiella E., Procopio A., et al. l-carnitine addition to dialysis fluid. A therapeutic alternative for hemodialysis patients. Nephron 51 (1989) 237-242
74. Vaz F.M., and Wanders R.J.A. Carnitine biosynthesis in mammals. Biochem J 361 (2002) 417-429
75. Veselá E., Racek J., Trefil L., Jankovy'ch V., and Pojer M. Effect of l-carnitine supplementation in hemodialysis patients. Nephron 88 (2001) 218-223
76. Wahba I.M., and Mak R.H. Obesity and obesity-initiated metabolic syndrome: Mechanistic links to chronic kidney disease. Clin J Am Soc Nephrol 2 (2007) 550-562
77. Wutzke K.D., and Lorenz H. The effect of l-carnitine on fat oxidation, protein turnover, and body composition in slightly overweight subjects. Metabolism 53 (2004) 1002-1006
78. Zammit V.A. Carnitine acyltransferases: Functional significance of subcellular distribution and membrane topology. Progr Lipid Res 38 (1999) 199-224
79. Zimmermann G.R., Lehár J., and Keith C.T. Multi-target therapeutics: When the whole is greater than the sum of the parts. Drug Discov Today 12 (2007) 34-42