Functional domains of gene expression are established and maintained along the cephalocaudal axis of the mouse intestine despite rapid and perpetual renewal of its epithelium. One such functional domain is associated with active absorption of bile acids in the ileum. This project will examine the functional interactions of two components of the sodium-dependent, active bile acid transport system: the ileal brush border membrane bile acid transporter (IBAT) and the cytosolic ileal lipid binding protein (ILBP).
The specific aims of this proposal are to: 1) examine the cell lineage-specific, regional, and development patterns of IBAT and ILBP gene expression in the intact gut of FVB/N mice and in intestinal isografts; 2) use well characterized transcriptional regulatory elements from the fatty acid binding protein genes (Fabps) to redirect expression of IBAT and/or ILBP to duodenal and jejunal villus- associated enterocytes in transgenic mice and assess whether these regions of the gut acquire the ability to actively transport luminal bile acids; and 3) determine the functional contributions of ILBP to bile acid transport by generating and characterizing mice that are homozygous for Ilbp null alleles. The proposed gain of function studies using transgenic mice will provide in vivo evidence for the functional activity of IBAT and ILBP in alternate positions and developmental stages within the intestine. Further characterization of the IBAT protein brush border membrane protein is necessary for the rationale design of potential transport inhibitors. Such modulation of bile acid and fat absorption may also provide a basis for the rational design of new therapeutic strategies to modulate absorption of cholesterol and bile acids in humans and thus impact upon coronary artery disease. Further characterization of this biologically important pathway should also lead to an understanding of the pathogenetic mechanisms that affect individuals suffering from developmental defects in the enterohepatic circulation of bile salts. These studies may promote new strategies toward augmentation of bile acid absorption in other regions of the bowel especially for individuals suffering from ileal atresia or who have undergone ileal resections secondary to severe inflammatory bowel disease.
