title: L-carnitine: A nutritional modulator of glucocorticoid receptor functions.
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.
authors.affiliation: Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1583, USA. alescis@mail.nih.gov
authors.forename: Salvatore
authors.initials: S
authors.lastname: Alesci
authors.forename: Massimo U
authors.initials: MU
authors.lastname: De Martino
authors.forename: Marco
authors.initials: M
authors.lastname: Mirani
authors.forename: Salvatore
authors.initials: S
authors.lastname: Benvenga
authors.forename: Francesco
authors.initials: F
authors.lastname: Trimarchi
authors.forename: Tomoshige
authors.initials: T
authors.lastname: Kino
authors.forename: George P
authors.initials: GP
authors.lastname: Chrousos
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002331:Carnitine / Q000378:metabolism / Q000494:pharmacology*; D002467:Cell Nucleus / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018664:Interleukin-12 / Q000096:biosynthesis; D008954:Models, Biological; D009000:Monocytes / Q000187:drug effects / Q000276:immunology; D011965:Receptors, Glucocorticoid / Q000378:metabolism* / Q000502:physiology; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C411470:glucocorticoid receptor alpha; D018664:Interleukin-12; D002331:Carnitine