The nutrigenomic metabolite L‑carnitine directly modulates the activity and expression of nuclear receptors in adipocytes, liver and muscle cells

Abstract

Background: L-carnitine is an indispensable metabolite in eukaryotic cells, which facilitates transport of long-chain fatty acids into the mitochondrial matrix for subsequent β-oxidation and helps to safeguard the acetyl-CoA level. Additionally, L-carnitine has been proven to exert a nutrigenomic effect, modulating the expression of numerous target genes. However, the diverging time-dependent effects of short-term and extended L-carnitine supplementation have not been investigated in more detail yet, especially in the interplay of adipocytes, liver and muscle cells. A cell culture model with conditions of L-carnitine deficiency and supplementation for these cell types was established to investigate the effects of L-carnitine on key nuclear receptors and their pathways.Results: L-carnitine deficiency as well as L-carnitine supplementation to hepatocytes modulated protein activity of multiple nuclear receptor pathways (RAR, RXR, VDR, PPAR, HNF4, ER, LXR). On the transcriptional level, short-term L-carnitine supplementation initially exerted an inhibitory effect on the steady state mRNA levels of PPAR-α, PPAR-δ, PPAR-γ, RAR-β , LXR-α and RXR-α in adipocytes, liver and muscle cells. However, extended L-carnitine supplementation for 24 and 48 hours led to a significant upregulation of PPAR-α and PPAR-δ , being key regulators of lipid catabolism, thereby promoting lipolysis and β-oxidation. In addition, significant differences in transcriptional modulation were found between adipocytes, liver and muscle cells. Extended L-carnitine administration to hepatocytes also modulated mRNA expression levels of nuclear receptor target genes CYP2R1 , ALDH1A1 , HSD11B2 , OGT and HMGCR.Conclusions: These findings show a clear nutrigenomic effect of L-carnitine on the protein activity and expression levels of selected nuclear receptors in different tissues, promoting lipolytic gene expression as well as decreasing transcription of adipogenic and insulin-resistance linked genes. Therefore L-carnitine supplementation obviously is a promising strategy supporting established antihyperlipidemic therapies. BackgroundLcarnitine (L3hydroxy4N-trimethylaminobutyrate) is a quaternary ammonium compound and an indispensable metabolite in all eukaryotic cells. Lcarnitine is synthesized from the essential amino