Adaptive regulation of intestinal folate uptake: effect of dietary folate deficiency

Abstract

Folate is an essential micronutrient that, in mammals, must be obtained from exogenous sources via intestinal absorption. Previous studies have characterized different aspects of the mechanism of the intestinal folate uptake process. Much less, however, is known about regulation of this process. In this study, we examined the effect of dietary folate deficiency on intestinal folate uptake using the rat as an animal model. The results showed that dietary folate deficiency leads to a significant (P < 0.01) and specific upregulation in the transepithelial transport of folic acid. The upregulation in transepithelial folate transport 1) was found to be due to an induction in carrier-mediated folate uptake across the brush-border membrane (BBM) and was mediated via a significant (P < 0.01) increase in the maximal velocity but not the apparent Michaelis constant of the uptake process, 2) was associated with a marked increase in the steady-state mRNA level of reduced folate carrier-1 and in the level of the expressed protein at the intestinal BBM, and 3) was associated with a marked (>10-fold) increase in the activity of the intestinal BBM form of folate hydrolase. Results of this study demonstrate, for the first time, that dietary folate deficiency leads to a marked upregulation in intestinal folate uptake and in the activity of folate hydrolase. Furthermore, the upregulation in folate uptake is associated with an increase in mRNA and protein levels of folate carrier, suggesting possible involvement of a transcriptional regulatory mechanism(s) in the upregulation.

High‐affinity folate receptor in cardiac neural crest migration: A gene knockdown model using siRNA

“…The short-term negative impact of this procedure upon total Folr1 expression supports the finding of Saitsu et al (2003) and Sato et al (2008), where the site of neural tube closure/neural crest formation also is a principal site of Folr1 expression in the early (2-10 somite) embryo. The apparent rebound effect of the Folr1 expression that occurred between 48 and 96 hr subsequent its initial knockdown is consistent with the magnitude of Folr1 up-regulation that can occur within 8 hr of the onset of a folate deficiency in several cell lines or in kidney cells (Hsueh and Dolnick, 1993;Said et al, 2000;Zhu et al, 2001;Sadasivan et al, 2002;Antony et al, 2004). Additionally, the expression of the folate receptor can be induced during folate insufficiency in some tissues where it is not normally expressed (Xiao et al, 2005).…”

Characterization of a Folate Transporter in HeLa Cells with a Low pH Optimum and High Affinity for Pemetrexed Distinct from the Reduced Folate Carrier

“…However, recent studies from this laboratory indicate that in human solid tumors, in general, there is very prominent transport activity at low pH that is usually equal to or often exceeds transport mediated by RFC at physiologic pH (9). The mechanism(s) underlying this low pH transport activity has not been clarified, although there is some evidence suggesting that in cells of intestinal origin this transport activity is related, at least in part and in some way, to RFC (11)(12)(13)(14). This study addresses the mechanism of folate transport at low pH using a HeLa cell line with prominent low pH activity in which RFC was deleted from the genome and therefore cannot contribute at all, qualitatively or quantitatively, to the transport characteristics observed.…”

Moderate folate depletion modulates the expression of selected genes involved in cell cycle, intracellular signaling and folate uptake in human colonic epithelial cell lines

“…Previous studies have shown that Folate Receptor 1 (FOLR1) [33][34][35][36] is up-regulated due to folate depletion in vitro, while it is the reduced folate carrier (RFC) that is upregulated in the rat intestine [37,38], with the FOLR1 remaining undetectable [38]. Increased FOLR1 in vitro and the increased RFC in vivo reflect the abundance of available forms in the particular model and the affinity of each protein for them.…”