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Nuclear respiratory factor 1 (NRF‐1) upregulates the expression and function of reduced folate carrier (RFC) at the blood‐brain barrier
Author(s) -
Alam Camille,
Hoque Md. Tozammel,
Sangha Vishal,
Bendayan Reina
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202000239rr
Subject(s) - choroid plexus , chromatin immunoprecipitation , downregulation and upregulation , folate receptor , transcription factor , calcitriol receptor , blood–brain barrier , chemistry , microbiology and biotechnology , biology , receptor , biochemistry , gene expression , promoter , central nervous system , endocrinology , gene , genetics , cancer , cancer cell
Folates are important for neurodevelopment and cognitive function. Folate transport across biological membranes is mediated by three major pathways: folate receptor alpha (FRα), proton‐coupled folate transporter (PCFT), and reduced folate carrier (RFC). Brain folate transport primarily occurs at the choroid plexus through FRα 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‐1α 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‐1α 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 the SLC19A1 promoter, 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‐1α activation by PQQ upregulates RFC functional expression at the BBB and could potentially enhance brain folate uptake.