Vukić Maja, Neme Antonio, Seuter Sabine, Saksa Noora, de Mello Vanessa D F, Nurmi Tarja, Uusitupa Matti, Tuomainen Tomi-Pekka, Virtanen Jyrki K, Carlberg Carsten
School of Medicine, Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
PLoS One. 2015 Apr 13;10(4):e0124339. doi: 10.1371/journal.pone.0124339. eCollection 2015.
Vitamin D3 has transcriptome- and genome-wide effects and activates, via the binding of its metabolite 1α,25-dihydroxyvitamin D3 to the transcription factor vitamin D receptor (VDR), several hundred target genes. Using samples from a 5-month vitamin D3 intervention study (VitDmet), we recently reported that the expression of 12 VDR target genes in peripheral blood mononuclear cells (PBMCs) as well as 12 biochemical and clinical parameters of the study participants are significantly triggered by vitamin D3. In this study, we performed a more focused selection of further 12 VDR target genes and demonstrated that changes of their mRNA expression in PBMCs of VitDmet subjects significantly correlate with alterations of 25-hydroxyvitamin D3 serum levels. Network and self-organizing map analysis of these datasets together with that of the other 24 parameters was followed by relevance calculations and identified changes in parathyroid hormone serum levels and the expression of the newly selected genes STS, BCL6, ITGAM, LRRC25, LPGAT1 and TREM1 as well as of the previously reported genes DUSP10 and CD14 as the most relevant parameters for describing vitamin D responsiveness in vivo. Moreover, parameter relevance ranking allowed the segregation of study subjects into high and low responders. Due to the long intervention period the vitamin D response was not too prominent on the level of transcriptional activation. Therefore, we performed in the separate VitDbol trial a short-term but high dose stimulation with a vitamin D3 bolus. In PBMCs of VitDbol subjects we observed direct transcriptional effects on the selected VDR target genes, such as an up to 2.1-fold increase already one day after supplementation onset. In conclusion, both long-term and short-term vitamin D3 supplementation studies allow monitoring the vitamin D responsiveness of human individuals and represent new types of human in vivo vitamin D3 investigations.
维生素D3具有全转录组和全基因组效应，并通过其代谢产物1α,25 - 二羟基维生素D3与转录因子维生素D受体（VDR）结合，激活数百个靶基因。利用一项为期5个月的维生素D3干预研究（VitDmet）的样本，我们最近报告称，维生素D3可显著触发外周血单核细胞（PBMC）中12个VDR靶基因的表达以及研究参与者的12项生化和临床参数。在本研究中，我们对另外12个VDR靶基因进行了更有针对性的筛选，并证明VitDmet受试者PBMC中它们的mRNA表达变化与25 - 羟基维生素D3血清水平的改变显著相关。对这些数据集以及其他24个参数进行网络和自组织映射分析，随后进行相关性计算，确定甲状旁腺激素血清水平的变化以及新选择的基因STS、BCL6、ITGAM、LRRC25、LPGAT1和TREM1以及先前报道的基因DUSP10和CD14的表达是描述体内维生素D反应性的最相关参数。此外，参数相关性排名允许将研究对象分为高反应者和低反应者。由于干预期较长，维生素D反应在转录激活水平上不太突出。因此，我们在单独的VitDbol试验中进行了一次短期但高剂量的维生素D3推注刺激。在VitDbol受试者的PBMC中，我们观察到对所选VDR靶基因的直接转录效应，例如在补充开始后一天就有高达2.1倍的增加。总之，长期和短期维生素D3补充研究都可以监测个体的维生素D反应性，代表了新型的人体维生素D3体内研究。
