Function of ileal lipid binding proteins

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Fatty acid binding proteins (FABPs) are abundant, small molecular weight soluble proteins found in various tissues. To date, the FABP family has 9 members that bind small hydrophobic compounds. Each FABP has a distinct ligand specificity and is associated with certain tissues. FABPs have similar three dimensional structures despite significant dissimilarity in primary structures which likely contributes to their characteristic ligand preferences. Loss-of-function mutations gave important insights into FABP function in a variety of metabolic processes, but the precise molecular functions of FABPs are still not well understood. These proteins may act as cellular storage depots, intracellular transporters for their respective ligands, and serve as intracellular shuttles between the membrane-bound transporter that internalize their ligands and the cognate nuclear receptors bound to gene promoters.******Fabp6 was first identified in the distal portion of the small intestine. This FABP type binds both bile acids and fatty acids, but shows a preference for bile acids. Bile acids are synthesized by the liver from cholesterol, and are needed for absorption of lipids and lipid-soluble nutrients. These compounds have emerged as important regulators of gene expression by serving as modulating ligands for the nuclear receptor farnesoid x receptor and the G-protein coupled receptor TGR5.  Recently, we showed that Fabp6 is needed for transport of conjugated bile acid in ileal enterocytes. Mice lacking Fabp6 show enhanced bile acid excretion, exposing the large intestine to higher than normal concentrations of bile acids. Given the bacteriostatic/bactericidal activity of bile acids, it is likely that exposure of gut bacteria in the large intestine to excess bile acids remodels the gut microbiome. As well, the differing binding affinities of various bile acids species to FABP6 may have a large influence on the type of bile acids released into the large intestine. Fabp6 mRNA has been detected in other tissues (such as ovaries), raising the possibility that this protein may have biological functions beyond its documented roles in the metabolism of bile acids in the small intestine.******The proposed research program has 3 themes: ***In Theme I, we will investigate the ligand preferences of different Fabp6 species, and the impact of Fabp6 in modulating the regulatory potential of different bile acid species. In Theme II, we will analyze the biological importance of Fabp6 in non-intestinal cells. In Theme III, we will study the consequences of the loss of ileal Fabp6 function on the gut microbiota and nutrition, and the capacity of the microbiota to metabolize bile acids.  ******This program will yield new insights on Fabp6 biology, the importance of Fabp6 in metabolism, as well as advance our general understanding of FABP function.*** **