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

Folate is an essential micronutrient that, in mammals, must be obtained fro m exogenous sources via intestinal absorption. Previous studies have charac terized 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 intestin al 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 up regulation 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) a nd was mediated via a significant (P < 0.01) increase in the maximal veloci ty but not the apparent Michaelis constant of the uptake process, 2) was as sociated with a marked increase in the steady-state mRNA level of reduced f olate 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 activi ty of the intestinal BBM form of folate hydrolase. Results of this study de monstrate, for the first time, that dietary folate deficiency leads to a ma rked upregulation in intestinal folate uptake and in the activity of folate hydrolase. Furthermore, the upregulation in folate uptake is associated wi th an increase in mRNA and protein levels of folate carrier, suggesting pos sible involvement of a transcriptional regulatory mechanism(s) in the upreg ulation.