Upregulation of reduced folate carrier by vitamin D enhances brain folate uptake in mice lacking folate receptor alpha

Abstract

Folates are critical for central nervous system function. Folate transport is mediated by 3 major pathways, reduced folate carrier (RFC), proton-coupled folate transporter (PCFT), and folate receptor alpha (FRα/Folr1), known to be regulated by ligand-activated nuclear receptors. Cerebral folate delivery primarily occurs at the choroid plexus through FRα and PCFT; inactivation of these transport systems can result in very low folate levels in the cerebrospinal fluid causing childhood neurodegenerative disorders. These disorders have devastating effects in young children, and current therapeutic approaches are not sufficiently effective. Our group has previously reported in vitro that functional expression of RFC at the blood–brain barrier (BBB) and its upregulation by the vitamin D nuclear receptor (VDR) could provide an alternative route for brain folate uptake. In this study, we further demonstrated in vivo, using Folr1 knockout (KO) mice, that loss of FRα led to a substantial decrease of folate delivery to the brain and that pretreatment of Folr1 KO mice with the VDR activating ligand, calcitriol (1,25-dihydroxyvitamin D3), resulted in over a 6-fold increase in [13C5]-5-formyltetrahydrofolate ([13C5]-5-formylTHF) concentration in brain tissues, with levels comparable to wild-type animals. Brain-to-plasma concentration ratio of [13C5]-5-formylTHF was also significantly higher in calcitriol-treated Folr1 KO mice (15-fold), indicating a remarkable enhancement in brain folate delivery. These findings demonstrate that augmenting RFC functional expression at the BBB could effectively compensate for the loss of Folr1-mediated folate uptake at the choroid plexus, providing a therapeutic approach for neurometabolic disorders caused by defective brain folate transport.

Nuclear respiratory factor 1 (NRF‐1) upregulates the expression and function of reduced folate carrier (RFC) at the blood‐brain barrier

“…27 In our studies, we found that PQQ administration did not result in systemic toxicity as evident by the lack of weight loss among PQQ-treated animals ( Figure 7A). This is in contrast to our previous study with VDR, 16 where exogenous administration of calcitriol resulted in significant weight loss and hypercalcemia due to VDR-mediated transactivation of renal and intestinal calcium ion channels. 32 Most importantly, we confirmed that Slc19a1 (RFC) mRNA expression was significantly induced in various tissues of mice treated with PQQ, particularly in isolated brain capillaries that are representative of the BBB ( Figure 7B).…”

Integration of Airway Inflammation and Remodeling Mechanisms Specific to Eosinophilic Asthma Through Differential Co-Expression of Genes in Bronchial Brush Biopsy Samples

“…Up-regulation of SLC19A1 may be driven by transcription factors linked to asthma (CEBPB, USF1, SP1), Th2-differentiation (CEBPB) 122 and asthma-speci c mitochondrial biogenesis (NRF-1). Furthermore, it is up-regulated by vitamin D 129 , which de ciency was previously linked to asthma control. Differential coexpression in EA may indicate both activity of the above transcription factors, cell proliferation status or impaired reaction to folate de ciency, a condition under which SLC19A1 is considered cytotoxic, since it may aggravate folate deprivation by expulsion of folate monoglutamates 130 .…”

This was the year that was: brain barriers and brain fluid research in 2019

“…The importance of understanding the mechanisms regulating BBB/NVU function is highlighted in a recent study on folate transport by Alam et al [51]. Folate transport at the choroid plexus involves proton-coupled folate transport and folate receptor alpha and interference with such transport causes low CSF folate levels and neurodegeneration.…”

“…Folate transport at the choroid plexus involves proton-coupled folate transport and folate receptor alpha and interference with such transport causes low CSF folate levels and neurodegeneration. Alam et al [51] found that upregulating the reduced folate transporter at the BBB, by activating the vitamin D nuclear receptor with calcitriol, could compensate for the loss of choroid plexus transport.…”