Submitted to: Gastroenterology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/24/2001
Publication Date: 5/1/2002
Citation: Hwang, S.T., Urizar, N.L., Moore, D.D., Henning, S.J. 2002. Bile acids regulate the ontogenic expression of ileal bile acid binding protein in the rat via the farnesoid X receptor. Gastroenterology. 122(5):1483-1492. Interpretive Summary: Ileal bile acid binding protein (IBABP) is a useful marker for intestinal maturation, a significant problem in premature infants. To determine if a bile acid receptor, the farnesoid X receptor (FXR), plays a role in the expression of IBABP, we studied rats fed with taurocholate, a bile acid (BA), with those fed a normal diet. Analysis of intestinal material showed that FXR increased from birth to postnatal week 3, and BAs play a role in normal development of IBABP through FXR activation. These findings will direct future studies on gastrointestinal maturation of premature human infants.
Technical Abstract: In the rat, an increase in ileal bile acid binding protein (IBABP) expression occurs during the third postnatal week. In vitro studies suggest that bile acids (BAs) increase IBABP transcription by activating the BA receptor, farnesoid X receptor (FXR). Thus, we investigated the role of BAs on the ontogenic expression of IBABP and whether FXR may mediate these effects. Suckling rats were gavage-fed taurocholate for 3 days or were allowed to develop normally. Ileums were collected for Northern and Western blot analyses. Electrophoretic mobility shift assays for functional FXR were performed using nuclear extracts from ileums of both adult and developing rats. Taurocholate gavage significantly elevated IBABP messenger RNA and protein levels in suckling animals. Gelshift assays using adult ileal nuclear extracts incubated with a radiolabeled consensus inverted repeat-1 oligonucleotide (response element for FXR) revealed a high-molecular weight DNA/protein complex. Cold competition and supershift assays showed that this complex is sequence specific and confirmed that FXR is a component of the complex. Gelshift assays with nuclear extracts from rat ileum at different ages revealed absence of the DNA/protein complex in the second postnatal week when there is lack of IBABP expression and presence of these complexes at later ages when there is normally high expression. Western blot analyses showed FXR and its heterodimer partner, retinoid X receptor alpha, protein levels are low in the ileum during the suckling period and increase during the third postnatal week. BAs play a role in the normal developmental expression of IBABP through FXR activation, and decreased functional FXR in ileal nuclei during the suckling period may account, in part, for the lack of IBABP expression at this time.