Regulation of Reduced Folate Carrier (RFC) by Vitamin D Receptor at the Blood-Brain Barrier

Alam, Camille; Hoque, Tozammel; Finnell, Richard H.; Goldman, I. David; Bendayan, Reina

doi:10.1021/acs.molpharmaceut.7b00572

Cited by 41 publications

(59 citation statements)

References 53 publications

(148 reference statements)

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“…Furthermore, induction of RFC via interactions with specific nuclear receptors, such as VDR, may enhance transport of folate into the brain. Several groups, including ours, have confirmed the presence of RFC in human (14,15) and rodent (16) BBB, and demonstrated active transport of folates in various BBB model systems, including isolated human brain capillaries (17), immortalized human cell lines (hCMEC/D3), and rat (RBE4) cerebral microvessel endothelium (14,15). The objective of the current study was to investigate the role of VDR in the regulation of RFC in vivo, using a FRα/Folr1 knockout (KO) mouse model.…”

Section: Significancesupporting

confidence: 61%

“…Finding new approaches for enhancing brain folate delivery may have a significant impact on the treatment of childhood neurometabolic disorders caused by folate deficiency. Our group has reported that the vascular BBB could present an alternative route for brain folate transport, especially when inactivation of FRα or PCFT impairs the major route of folate uptake at the choroid plexus (14). We further demonstrated in vitro that functional expression of another folate transporter, RFC, and its upregulation by the VDR nuclear receptor could potentially increase folate transport across the BBB (14).…”

Section: Discussionmentioning

confidence: 83%

“…Localization of Folate Receptor/Transporters in Mouse BBB. Our laboratory has previously reported robust expression of RFC, PCFT, and/FRα in several in vitro models of human and rodent BBB (14). In this study, we further investigated the cellular localization of the 3 major folate transport pathways in primary cultures of mouse brain microvascular endothelial cells by confocal microscopy (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Mouse Brain Capillary Isolation. Brain capillaries were isolated from adult male or female LM/Bc mice (8 to 12 wk old) as described previously (14,18). Mice were anesthetized through isoflurane inhalation and decapitated once a deep anesthetic surgical plane was achieved.…”

Section: Methodsmentioning

confidence: 99%

“…Eloranta et al (13) demonstrated that treatment of intestinal Caco-2 cells and isolated rat duodenum with the VDR-activating ligand, 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 or calcitriol] induced SLC46A1/Slc46a1 (PCFT) messenger RNA (mRNA) expression, which subsequently increased folic acid uptake. Recently, our laboratory has also examined the role of VDR in the regulation of RFC at the blood-brain barrier (BBB) (14). We provided evidence that activation of VDR through calcitriol exposure upregulates RFC mRNA and protein expression, as well as function, in immortalized cultures of human brain microvessel endothelial cells (hCMEC/D3) and isolated mouse brain capillaries that are representative of the BBB.…”

Section: Significancementioning

confidence: 99%

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

Alam

Aufreiter

Georgiou

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Section: Significancesupporting

confidence: 61%

Section: Discussionmentioning

confidence: 83%

Section: Resultsmentioning

confidence: 98%

Section: Methodsmentioning

confidence: 99%

Section: Significancementioning

confidence: 99%

See 3 more Smart Citations

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

Alam

Aufreiter

Georgiou

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Drug Transport in the Brain

et al. 2022

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Effectiveness of B Vitamins and Their Interactions with Aspirin in Improving Cognitive Functioning in Older People with Mild Cognitive Impairment: Pooled Post-Hoc Analyses of Two Randomized Trials

Smith

Refsum

et al. 2021

The Journal of nutrition, health and aging

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Background and Objectives A randomized placebo-controlled trial found a significant negative interaction between aspirin and B vitamins in cognitive functioning in older people with mild cognitive impairment (MCI). To validate this finding, we pooled data of this trial with that of a similar B-vitamin trial (VITACOG) to examine the effectiveness of B vitamins and their interactions with aspirin in improving global cognitive functioning and slowing brain atrophy in older people with MCI. Design Pooled post-hoc analyses of two randomized placebo-controlled trials. Participants In total, 545 older people with MCI were included in the study. Intervention Placebo or B-vitamin supplements (vitamin B12, folic acid with or without vitamin B6) for 24 months. Measurements The primary outcome was the Clinical Dementia Rating scale-global score (CDR-global). The secondary outcomes were CDR-sum of box score (CDR-SOB), memory Z-score, executive function Z-score, and whole brain atrophy rate. Results 71 (26.2%) and 83 (30.3%) subjects in the active and placebo group respectively were aspirin users. Overall, B vitamins reduced whole brain atrophy rate significantly (P = 0.003), but did not have significant effect on CDR-global, CDR-SOB, memory and executive function. Aspirin use had significant negative interaction effects on B vitamins in CDR-global and CDR-SOB (Beta = 0.993, P = 0.038, and Beta = 0.583, P = 0.009, respectively), but not in memory or executive function Z-scores. Among aspirin non-users, B-vitamin group subjects had more favourable changes in CDR-global and CDR-SOB (P = 0.019 and 0.057, respectively). B vitamins significantly slowed brain atrophy in aspirin non-users (P = 0.001), but not in aspirin users, though the interaction term was not significant (Beta = 0.192, P = 0.276). Conclusion In older people with MCI, B vitamins had significantly favourable effects on global cognitive functioning and whole brain atrophy rate in those who were not taking aspirin, but not in aspirin users.

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Regulation of Reduced Folate Carrier (RFC) by Vitamin D Receptor at the Blood-Brain Barrier

Cited by 41 publications

References 53 publications

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

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

Drug Transport in the Brain

Effectiveness of B Vitamins and Their Interactions with Aspirin in Improving Cognitive Functioning in Older People with Mild Cognitive Impairment: Pooled Post-Hoc Analyses of Two Randomized Trials

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