A functional analysis of liver‐ and intestinal fatty acid binding proteins in the intestinal enterocyte

The fatty acid binding protein (FABP) family consists of 14-15 kD cytoplasmic proteins, which are abundantly expressed in various mammalian tissues. In the enterocyte, two FABPs are present: Liver-type FABP (LFABP; FABP1), and Intestinal FABP (IFABP; FABP2). Previous studies in chow-fed mice did not reveal marked differences between IFABP or LFABP null mice, thus we hypothesized that feeding high-fat diets would provide a lipid overload to the intestine, perhaps revealing phenotypic differences that would provide insight into the individual functions of LFABP and IFABP. We directly compared IFABP−/−, LFABP−/−, and WT mice fed low or high fat diets. Changes in mucosal lipid metabolism were observed, with a decrease in FA incorporation into triacylglycerol (TG) relative to phospholipid (PL) in IFABP−/− mice, and reduced monoacylglycerol incorporation in TG relative to PL and reduced FA oxidation in LFABP−/− mice. Striking changes in whole body phenotypes were found: LFABP−/− mice fed a high-fat diet had greater weight gain and fat mass relative to WT, while IFABP−/− mice remained lean. Respiratory exchange ratios suggest that high-fat fed LFABP−/− mice preferentially oxidize lipids, while IFABP−/− mice preferentially metabolize carbohydrate as a fuel source. IFABP-/- mice are healthy with a lean phenotype, whereas LFABP-/- mice are obese but are otherwise metabolically normal. To further elucidate the individual and overlapping functions of enterocyte FABPs, we generated a novel strain of mice that were null for both IFABP and LFABP (DKO). The phenotype of DKO mice fed a high-fat diet was integrated between LFABP-/- and IFABP-/- mice, with body weights and composition in between the single knockout mice. DKO mice fed a high-fat diet were similar to IFABP-/- mice in primarily using carbohydrate for energy. It was also observed that DKO mice were less active relative to WT mice. Importantly, there were no differences between groups in fecal lipids, suggesting that LFABP and IFABP are not involved with bulk FA uptake into the intestine. Overall, the results of these studies strongly suggest that IFABP and LFABP have different functions in intestinal lipid metabolism, which result in downstream alterations in whole body energy metabolism.