L-carnitine is an essential nutrient with a major role in cellular energy production. There is evidence that, at high doses, L-carnitine might mimic some of the biological activities of glucocorticoids, especially immunomodulation. To explore the molecular basis of this effect, we tested the influence of L-carnitine on glucocorticoid receptor-alpha (GRalpha) functions. Millimolar concentrations of L-carnitine, which were not cytotoxic in vitro, significantly reduced the whole cell binding of [3H]dexamethasone to GRalpha by decreasing the affinity of this receptor for its steroid ligand. At the same concentrations, L-carnitine was able to trigger nuclear translocation of green fluorescent protein (GFP)-fused human GRalpha and transactivate the glucocorticoid-responsive mouse mammary tumor virus (MMTV) and TAT3 promoters in a dose-dependent fashion. This effect was solely dependent on the presence of glucocorticoid-responsive elements on the promoter and on the expression of functional GRalpha by the cell. Finally, similarly to glucocorticoids, L-carnitine suppressed tumor necrosis factor-alpha (TNFalpha) and interleukin-12 release by human primary monocytes stimulated with lipopolysaccharide ex vivo. Both GRalpha transactivation and cytokine suppression by L-carnitine were abrogated by the GRalpha-antagonist RU 486. Taken together, our results suggest that pharmacological doses of L-carnitine can activate GRalpha and, through this mechanism, regulate glucocorticoid-responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids.

L-Carnitine: a nutritional modulator of glucocorticoid receptor functions

BENVENGA, Salvatore;TRIMARCHI, Francesco;
2003

Abstract

L-carnitine is an essential nutrient with a major role in cellular energy production. There is evidence that, at high doses, L-carnitine might mimic some of the biological activities of glucocorticoids, especially immunomodulation. To explore the molecular basis of this effect, we tested the influence of L-carnitine on glucocorticoid receptor-alpha (GRalpha) functions. Millimolar concentrations of L-carnitine, which were not cytotoxic in vitro, significantly reduced the whole cell binding of [3H]dexamethasone to GRalpha by decreasing the affinity of this receptor for its steroid ligand. At the same concentrations, L-carnitine was able to trigger nuclear translocation of green fluorescent protein (GFP)-fused human GRalpha and transactivate the glucocorticoid-responsive mouse mammary tumor virus (MMTV) and TAT3 promoters in a dose-dependent fashion. This effect was solely dependent on the presence of glucocorticoid-responsive elements on the promoter and on the expression of functional GRalpha by the cell. Finally, similarly to glucocorticoids, L-carnitine suppressed tumor necrosis factor-alpha (TNFalpha) and interleukin-12 release by human primary monocytes stimulated with lipopolysaccharide ex vivo. Both GRalpha transactivation and cytokine suppression by L-carnitine were abrogated by the GRalpha-antagonist RU 486. Taken together, our results suggest that pharmacological doses of L-carnitine can activate GRalpha and, through this mechanism, regulate glucocorticoid-responsive genes, potentially sharing some of the biological and therapeutic properties of glucocorticoids.
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11570/1581074
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo

Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 40
  • ???jsp.display-item.citation.isi??? ND
social impact