Functional analysis of enterocyte-fatty acid binding proteins

The enterocyte fatty acid binding proteins (FABP), the liver FABP (LFABP, FABP1) and intestinal FABP (IFABP, FABP2) are members of small molecular weight 14-15kDa FABP family that are expressed in various mammalian tissues. LFABP is expressed in both the liver and the intestine while IFABP is solely expressed in the intestine. Previous studies in chow fed mice null for either LFABP (LFABP-/-) or IFABP (IFABP-/-) suggested that the two proteins are functionally distinct. Challenging LFABP-/- and IFABP-/- mice with high fat diet (HFD) revealed a divergent phenotype, underscoring functional differences. LFABP-/- mice appear to be a model for a metabolically healthy obese (MHO) phenotype, while IFABP-/- mice remained lean when compared to their respective wild-type (WT) control mice. In the present studies, the luminal bacteria content and its metabolite the short chain fatty acid (SCFA) were examined to assess whether there is a relationship between the observed dramatic whole-body phenotypic divergence of IFABP-/- and LFABP-/- mice and the gut microbiome. We found that the lean IFABP-/- mice had the shortest intestinal transit time, and higher fecal output and abundance of potentially beneficial bacterial guilds. By contrast, LFABP-/- mice were found to have a longer intestinal transit time, less fecal output and more bacterial guilds containing bacteria associated with obesity. Both IFABP-/- and LFABP-/- mice under both chow diet and HFD were found to have a higher levels of fecal SCFAs compared to the WT control mice. Thus, the alterations in gut bacterial communities and their metabolites are associated with many of the phenotypic changes observed in LFABP-/- and IFABP-/- mice. Since LFABP is expressed both in the liver and in the intestine, it is not clear whether the ablation of liver-LFABP, intestine-LFABP or the ablation of LFABP from both tissues is required to induce the MHO phenotype. In order to get a further insight into the role of liver-LFABP in the observed MHO phenotype, a conditional knock out LFABP mice (LFABP cKO) in which the gene was ablated only in the liver, was generated. Like HF fed whole-body LFABP-/- mice, liver-specific LFABP-/- (LFABPliv-/-) mice were found to have better capacity for endurance exercise when compared to their WT “floxed” controls (LFABPfl/fl) mice. Female LFABPliv-/- mice were found to be more obese after the HF feeding challenge, with greater body weight gain and fat mass (FM). However, despite their obesity, female LFABPliv-/- mice were protected against HFD induced hepatic steatosis. Thus, in female mice the liver specific ablation of LFABP is enough to induce the MHO phenotype observed in the whole body knockout mouse. Males, however, may require the ablation of either intestine-LFABP or both liver- and intestine-LFABP to induce the full MHO phenotype. Taken together, this work has revealed a role of the enterocyte FABPs in modulating intestinal bacterial content and its metabolites. Furthermore, these studies demonstrate a role of liver-LFABP in efficient hepatic uptake and trafficking of lipid in mice fed HFD.Ph.D.Includes bibliographical reference