title: Regulatory mechanisms of intestinal folate uptake in a rat model of folate oversupplementation.
abstract: Folic acid is essential for numerous biological functions, ranging from nucleotide biosynthesis to the remethylation of homocysteine. Folic acid is unable to cross the biological membranes by simple diffusion, so there exists a well-developed epithelial folate transport system for the regulation of normal folate homeostasis in the intestine. Any perturbances in the folate uptake system might lead to a state of folate deficiency, which in turn is strongly associated with the risk of various cancers, birth defects and CVD. Countries with obligatory folate fortification of food (USA and Canada) have documented a significant decrease in neural tube defects in newborns. However, the effect of folate oversupplementation on the intestinal absorption of folic acid has not been studied. We studied the process of folate transport and the expression of folate transporters in the rat intestine after folate oversupplementation. Rats were oversupplemented with tenfold the normal requirement of folic acid for periods of 10 and 60 d. Folate uptake in intestinal brush-border membrane vesicles followed saturable kinetics with pH optimum at 5·5. Acute, but not chronic, folate oversupplementation led to a significant down-regulation in intestinal folate uptake at acidic pH optima and was associated with a decrease in Vmax without any significant change in the Km of the folate uptake process. The decrease in folate uptake was also associated with the down-regulation in the protein levels of major folate transporters, proton-coupled folate transporter (PCFT) and reduced folate carrier (RFC), without altering their mRNA levels. Hence, it was concluded that acute folate oversupplementation results in a significant decrease in intestinal folate uptake by down-regulating the expressions of RFC and PCFT, via some post-transcriptional or translational mechanisms.
authors.affiliation: Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh 160 012, India.
authors.forename: Som
authors.initials: S
authors.lastname: Dev
authors.forename: Nissar
authors.initials: N
authors.lastname: Ahmad Wani
authors.forename: Jyotdeep
authors.initials: J
authors.lastname: Kaur
mesh_terms: D000818:Animals; D001692:Biological Transport; D019587:Dietary Supplements / Q000009:adverse effects*; D015536:Down-Regulation; D005492:Folic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D005494:Folic Acid Deficiency / Q000209:etiology*; D006863:Hydrogen-Ion Concentration; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D058979:Proton-Coupled Folate Transporter / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D058978:Reduced Folate Carrier Protein / Q000378:metabolism*; D014803:Vitamin B Complex / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D058979:Proton-Coupled Folate Transporter; D058978:Reduced Folate Carrier Protein; D014803:Vitamin B Complex; D005492:Folic Acid