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.

L-Carnitine ameliorates methotrexate-induced oxidative organ injury and inhibits leukocyte death

“…As evidenced in the present study, MTX administration resulted in increased serum TNF-α, indicating the role of this cytokine in drug-induced toxicity, while L-carnitine depressed the TNF-α response. Alesci et al (2003) showed that Lcarnitine suppressed TNF-α and interleukin-12 release by human primary monocytes when they were stimulated with lipopolysaccharides. It was previously shown that pretreatment with L-carnitine significantly blunted ethanol-induced stimulation of TNF-α release by isolated Kupffer cells (Bykov et al, 2003).…”

Relationship between Carnitine, Fatty Acids and Insulin Resistance

“…Alesci et al [26] reported that L -carnitine may act similarly to other tissue/gene-selective glucocorticoid receptor modulators. Pharmacological doses of L -carnitine can activate glucocorticoid receptor ␣ and, by this mechanism, regulate glucocorticoid-responsive genes.…”

Association of SLC22A4/5 Polymorphisms with Steroid Responsiveness of Inflammatory Bowel Disease in Japan

“…12 Based on our results, we hypothesize as follows: glucocorticoids exert their anti-inflammatory effect by interacting with an intranuclear glucocorticoid receptor α (GR-α). 25,26 Intracellular L-carnitine transported by OCTN1/2, activates allosterically GR-α resulting in its promotion to its intranuclear translocation, following transcriptional stimulation to induce anti-inflammatory responsive genes, such as IκBα or IL-10 in an L-carnitine dose-dependent fashion. [26][27][28] In summary, modulation of carnitine transportation can indirectly affect steroid responsiveness.…”

“…25,26 Intracellular L-carnitine transported by OCTN1/2, activates allosterically GR-α resulting in its promotion to its intranuclear translocation, following transcriptional stimulation to induce anti-inflammatory responsive genes, such as IκBα or IL-10 in an L-carnitine dose-dependent fashion. [26][27][28] In summary, modulation of carnitine transportation can indirectly affect steroid responsiveness. Specifically, steroid responsiveness in Japanese patients with Crohn's disease could be tuned by functional and/or transcriptional modulation of OCTN2 by the two-allele haplotype CG.…”