L-carnitine is an indispensable metabolite facilitating the transport of fatty acids into the mitochondrial matrix and has been previously postulated to exert a nutrigenomic effect. However, the underlying molecular mechanisms remain mostly unclear. We hypothesized that L-carnitine interacts with nuclear receptors involved in metabolic regulation, thereby modulating downstream targets of cellular metabolism. Therefore, we investigated the effect of L-carnitine supplementation on protein activity, mRNA expression, and binding affinities of nuclear receptors as well as mRNA expression of downstream targets in skeletal muscle cells, hepatocytes, and differentiated adipocytes. L-carnitine supplementation to hepatocytes increased the protein activity of multiple nuclear receptors (RAR, RXR, VDR, PPAR, HNF4, ER, LXR). Diverging effects on the mRNA expression of PPAR-α, PPAR-δ, PPAR-γ, RAR-β, LXR-α, and RXR-α were observed in adipocytes, hepatocytes, and skeletal muscle cells. mRNA levels of PPAR-α, a key regulator of lipolysis and β-oxidation, were significantly upregulated, emphasizing a role of L-carnitine as a promoter of lipid catabolism. L-carnitine administration to hepatocytes modulated the transcription of key nuclear receptor target genes, including ALDH1A1, a promoter of adipogenesis, and OGT, a contributor to insulin resistance. Electrophoretic mobility shift assays proved L-carnitine to increase binding affinities of nuclear receptors to their promoter target sequences, suggesting a molecular mechanism for the observed transcriptional modulation. Overall, these findings indicate that L-carnitine modulates the activity and expression of nuclear receptors, thereby promoting lipolytic gene expression and decreasing transcription of target genes linked to adipogenesis and insulin resistance.

中文翻译：

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左旋肉碱通过直接调节脂肪细胞、肝细胞和 SKMC 中的核受体信号发挥营养基因组作用，证明其对营养的影响

左旋肉碱是一种不可或缺的代谢物，可促进脂肪酸转运到线粒体基质中，以前曾假设它具有营养基因组学作用。然而，潜在的分子机制仍不清楚。我们假设左旋肉碱与参与代谢调节的核受体相互作用，从而调节细胞代谢的下游目标。因此，我们研究了左旋肉碱补充剂对蛋白质活性、mRNA 表达和核受体结合亲和力的影响，以及骨骼肌细胞、肝细胞和分化脂肪细胞中下游靶标的 mRNA 表达。向肝细胞补充左旋肉碱可增加多种核受体（RAR、RXR、VDR、PPAR、HNF4、ER、LXR）的蛋白质活性。在脂肪细胞、肝细胞和骨骼肌细胞中观察到对 PPAR-α、PPAR-δ、PPAR-γ、RAR-β、LXR-α 和 RXR-α mRNA 表达的不同影响。PPAR-α 的 mRNA 水平（脂肪分解和 β-氧化的关键调节因子）显着上调，强调了左旋肉碱作为脂质分解代谢促进剂的​​作用。向肝细胞施用左旋肉碱可调节关键核受体靶基因的转录，包括 ALDH1A1（脂肪生成的启动子）和 OGT（导致胰岛素抵抗的因素）。电泳迁移率变化试验证明左旋肉碱能增加核受体与其启动子靶序列的结合亲和力，表明观察到的转录调节的分子机制。总体，