Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier
Nuclear respiratory factor 1 (NRF-1) upregulates the expression and function of reduced folate carrier (RFC) at the blood-brain barrier
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DOI：
10.1096/fj.202000239rr
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发表时间：
2020-06-16
期刊：
影响因子：
4.8
通讯作者：
Bendayan, Reina
中科院分区：
文献类型：
--
作者：
Alam, Camille;Hoque, Md. Tozammel;Bendayan, Reina
叶酸对于神经发育和认知功能很重要。叶酸跨生物膜的转运由三个主要途径介导：叶酸受体α（FRα）、质子耦合叶酸转运蛋白（PCFT）和还原叶酸载体（RFC）。大脑叶酸转运主要通过 FR α 和 PCFT 在脉络丛发生；这些运输系统的失活会导致脑脊液 (CSF) 中的叶酸水平低于最佳水平，从而导致儿童神经系统疾病。我们的小组报道，通过与特定转录因子（即维生素 D 受体 (VDR)）相互作用，血脑屏障 (BBB) 上的 RFC 上调可以增加大脑叶酸的输送。本研究探讨了核呼吸因子 1 (NRF-1) 在 BBB RFC 调节中的作用。通过用其特异性配体吡咯喹啉醌 (PQQ) 处理来激活 NRF-1/PGC-1 α 信号传导，可显着诱导 hCMEC/D3 细胞中的 RFC 表达和转运活性。相反，用 NRF-1 或 PGC-1 α 靶向 siRNA 转染可下调同一细胞系统中 RFC 功能的表达。应用染色质免疫沉淀 (ChIP) 测定，我们进一步证明 PQQ 处理增加了 NRF-1 与编码 RFC 的 SLC19A1 启动子内假定的 NRF-1 结合位点的结合。此外，在离体小鼠脑毛细血管中用 PQQ 诱导 RFC 表达对野生型小鼠进行体内治疗。总之，这些发现表明 PQQ 激活 NRF-1/PGC-1 α 可上调 BBB 处的 RFC 功能表达，并可能增强大脑叶酸的吸收。
Folates are important for neurodevelopment and cognitive function. Folate transport across biological membranes is mediated by three major pathways: folate receptor alpha (FR alpha), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate transport primarily occurs at the choroid plexus through FR alpha and PCFT; inactivation of these transport systems results in suboptimal folate levels in the cerebrospinal fluid (CSF) causing childhood neurological disorders. Our group has reported that upregulation of RFC at the blood-brain barrier (BBB) through interactions with specific transcription factors, that is, vitamin D receptor (VDR) could increase brain folate delivery. This study investigates the role of nuclear respiratory factor 1 (NRF-1) in the regulation of RFC at the BBB. Activation of NRF-1/PGC-1 alpha signaling through treatment with its specific ligand, pyrroloquinoline quinone (PQQ), significantly induced RFC expression and transport activity in hCMEC/D3 cells. In contrast, transfection with NRF-1 or PGC-1 alpha targeting siRNA downregulated RFC functional expression in the same cell system. Applying chromatin immunoprecipitation (ChIP) assay, we further demonstrated that PQQ treatment increased NRF-1 binding to putative NRF-1 binding sites within theSLC19A1promoter, which encodes for RFC. Additionally, in vivo treatment of wild type mice with PQQ-induced RFC expression in isolated mouse brain capillaries. Together, these findings demonstrate that NRF-1/PGC-1 alpha activation by PQQ upregulates RFC functional expression at the BBB and could potentially enhance brain folate uptake.