The Effects of Folate Deficiency and Folic Acid Supplementation on Folate Absorption and Metabolism in a Mouse Model

Abstract

The effects of folate deficiency and folic acid (FA) supplementation on folate absorption and metabolism have not been well established in vivo. We investigated the effects of folate deficiency and FA supplementation on gene expression of folate receptors/transporters and metabolic enzymes in a mouse model. Postweaning C57BL/6 mice were randomized to receive diets containing 0 (moderate folate deficiency), 2 (control) or 20 mg FA/kg of diet for 3 months. Gene expression was assessed by real‐time RT‐qPCR. Plasma folate and unmetabolized FA and hepatic and small intestinal folate concentrations accurately reflected the supplemental levels of FA (p‐trend<0.0001). Expression of the proton‐coupled folate transporter (Pcft), reduced folate carrier (Rfc) and folate receptor‐1 (Folr1) in the small intestine and Folr1 in the liver was inversely associated with the supplemental levels of FA (p‐trend<0.0001). The supplemental levels of FA were inversely associated with thymidylate synthase (Tyms) expression in the liver and serine hydroxymethyltransferase (Shmt1) expression in the small intestine (p‐trend<0.05) but were not associated with the expression of dihydrofolate reductase (Dhfr) or methylenetetrahydrofolate reductase (Mthfr) in either tissue. Our data suggest that folate deficiency and FA supplementation modulate expression of genes involved in folate absorption and metabolism, likely as a homeostatic mechanism. However, FA supplementation may also adversely influence folate absorption and metabolism by dysregulation of these pathways.Supported by CIHR MOP#106446