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1 VA Medical Center, Long Beach, CA, USA; University of California, Irvine, CA, USA
* To whom correspondence should be addressed. E-mail: hmsaid{at}uci.edu.
Folate is an essential micronutrient that, in mammals, must be obtained from exogenous sources via intestinal absorption. Previous studies from our laboratory and others have demonstrated that folate absorption from the small intestine is mediated via the reduced-folate carrier (RFC). The goal of this study was to determine if the initial step of folate uptake by intestinal epithelial cells, i.e., transport across the brush border membrane (BBM) of the polarized enterocytes, is ontogenically regulated, and if so, to determine the molecular mechanism involved. Purified brush border membrane vesicles (BBMV) isolated from suckling, weanling, and adult rats were used in this study. The initial rate of carrier-mediated uptake of a physiological concentration of folic acid (0.1 µM) by jejunal BBMV was found to be significantly (P < 0.01) higher in suckling compared to weanling rats, which was in turn significantly (P < 0.01) higher than that in adult rats. This decline in carrier-mediated folate uptake with maturation was found to be mediated via a decrease in the Vmax of the folate uptake process (6.55 ± 0.87, 2.16 ± 0.10, 0.90 ± 0.16 pmol/mg protein/10 sec for suckling, weanling and adult rats, respectively), with no changes in its apparent Km. Western blot analysis of BBM protein and real time PCR showed RFC protein and mRNA levels, respectively, to be significantly (P < 0.01 for both) higher in suckling compared to weanling rats which were in turn significantly (P < 0.01 for both) higher than that in adult rats. These changes were found by nuclear run-on assay to be associated with a parallel decline in the RFC transcriptional rate in jejunal epithelia with maturation. In situ hybridization showed a similar pattern of RFC message distribution along crypt/villus axis in suckling and adult rat jejunum. These results demonstrate for the first time that folate transport across the intestinal BBM is under ontogenic regulation during early stages of life, and that this regulation involves a transcriptional regulatory mechanism(s).
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