Influence of carnitine on the miRNA expression profile in liver and skeletal muscle of growing pigs and its regulatory effects on different target transcripts.

最近的研究表明，肉碱是参与脂肪酸代谢的肉碱穿梭系统的辅助因子，补充肉碱可以改变猪肝脏和骨骼肌中的基因表达谱。此外，我们的观察表明，肉碱对参与脂肪代谢、葡萄糖摄取和葡萄糖氧化的基因的表达、IGF-1/PI3K/Akt信号通路、蛋白质周转和细胞凋亡具有多方面的影响。进一步的研究将揭示肉碱介导的基因和蛋白质调节的其他机制。目前，有研究使用不同的模式生物对其microRNA(MiRNA)表达谱进行了修饰，表明目标转录产物的翻译发生了变化，导致蛋白质合成受到抑制，从而导致了不同的表型修饰。这些变化取决于生物的种类、品种、组织和相应的发育阶段。最近的研究表明，营养成分和/或添加剂，如共轭亚油酸，可以影响miRNA转录组。这些研究结果表明，所研究的饲料添加剂直接改变特定miRNAs的表达，从而影响转录后基因调控，导致代谢的深刻变化。因此，我们假设肉碱也会影响miRNA的表达谱，导致多种代谢变化。这可能代表了肉碱在体内发挥多种作用的一种新的分子机制。为了研究肉碱的这些预期效应，我们必须阐明以下几个方面：肉碱补充或继发性肉碱缺乏在多大程度上改变了猪不同组织(肝脏、骨骼肌)的miRNA表达谱(问题1)。其次，在鉴定第一个实验中差异调控的miRNAs的基础上，必须研究miRNAs在其翻译过程中影响的下游靶标以及这种方式对个别途径的影响(问题2)。因此，计划中的项目有助于阐明肉碱在猪等农场动物中可能的、未知的分子作用机制。

Recent studies have shown that supplementation of carnitine, the cofactor of the carnitine shuttle system involved in fatty acid metabolism, alters the gene expression profile in liver and skeletal muscle of pigs. Furthermore, our observations demonstrate that carnitine exerts multiple effects on the expression of genes involved in lipid metabolism, glucose uptake and glucose oxidation, the IGF-1/PI3K/Akt-signalling pathway, the protein turnover and apoptosis. Further research will uncover additional mechanisms of carnitine-mediated gene and protein regulation. Presently there are studies using different model organisms modified in their microRNA (miRNA) expression profiles, showing an altered translation of target-transcripts, leading to a repression of protein synthesis which results in variable phenotypic modifications. These changes depend on the species, the breed, the tissue and the corresponding developmental stage of the organism. Recent studies show that nutritional ingredients and / or additives, such as conjugated linoleic acids can affect the miRNA transcriptome. The results of these studies indicate that the investigated feed additives directly alter the expression of specific miRNAs, thereby influencing the post-transcriptional gene regulation resulting in profound changes in metabolism. Consequently, we hypothesize that carnitine affects the miRNA expression profile leading to multiple metabolic changes, as well. This could represent a new molecular mechanism by which carnitine exerts its many effects in the body. To investigate these predicted effects of carnitine, we have to elucidate the following aspects: To what extent does carnitine supplementation or secondary carnitine deficiency modifies the miRNA expression profile in different tissues (liver, skeletal muscle) of pigs (question 1). Secondly, based on the identification of differentially regulated miRNAs from the first experiment, downstream targets which are influenced in their translation by miRNAs and the effects mediated in this way on individual pathways have to be investigated (question 2). Consequently, the planned project contributes to the elucidation of possible, unknown molecular mechanisms of action of carnitine in farm animals, like pigs.