Enterocyte fatty acid-binding proteins (FABPs): Different functions of liver and intestinal FABPs in the intestine☆

https://doi.org/10.1016/j.plefa.2014.10.001Get rights and content

Abstract

Fatty acid-binding proteins (FABP) are highly abundant cytosolic proteins that are expressed in most mammalian tissues. In the intestinal enterocyte, both liver- (LFABP; FABP1) and intestinal FABPs (IFABP; FABP2) are expressed. These proteins display high-affinity binding for long-chain fatty acids (FA) and other hydrophobic ligands; thus, they are believed to be involved with uptake and trafficking of lipids in the intestine. In vitro studies have identified differences in ligand-binding stoichiometry and specificity, and in mechanisms of FA transfer to membranes, and it has been hypothesized that LFABP and IFABP have different functions in the enterocyte. Studies directly comparing LFABP- and IFABP-null mice have revealed markedly different phenotypes, indicating that these proteins indeed have different functions in intestinal lipid metabolism and whole body energy homeostasis. In this review, we discuss the evolving knowledge of the functions of LFABP and IFABP in the intestinal enterocyte.

Section snippets

Fatty acid-binding proteins

The fatty acid-binding protein (FABP) family comprises 14–15 kD size intracellular proteins, which were discovered beginning in the 1970s [1], [2]. Presently, there are nine known FABPs that are present in high abundance (1–5%) in the cytosol of most tissues, plus the related cellular retinoid-binding proteins [3], [4]. The names for the proteins came from the tissue in which they were initially identified, but as some FABPs are expressed in multiple tissues, a numeric nomenclature is in use as

FABPs in the intestinal enterocyte

The intestinal enterocytes are responsible for processing the hydrolysis products of dietary lipids. Intestinal absorption of lipids is highly efficient, with greater than 95% of dietary lipid taken up [17]. It is generally thought that the presence of lipid-binding proteins is critical for this capacity, particularly because levels of FABPs are very high in cytosol [3]. In the intestinal enterocyte, two FABPs are present, largely in the absorptive intestinal villus cells, but not in crypt

Liver fatty acid-binding protein

LFABP is a highly abundant intracellular protein in the intestinal enterocyte. It is present throughout the intestine, but is most highly expressed in the duodenum and jejunum [29]. In vitro studies have shown that LFABP binds FA with high affinity, with Kd values in the nanomolar range [30], [31]. LFABP is also unique among the FABPs in that it has two FA-binding sites, and thus has a higher binding capacity than other FABPs. It has also been shown to bind to other lipid species, including

Intestinal fatty acid-binding protein

Unlike LFABP, IFABP is solely expressed in intestinal enterocytes of mammals. While IFABP is present throughout the small intestine, its highest expression is in the jejunum [56]. Like LFABP, IFABP is found widely distributed throughout the cytosol of the enterocyte during the fed state, but is localized toward the apical side of the cell in the fasted state [34]. IFABP has not been found to be involved with chylomicron formation [35], [57]; hence, IFABP has been proposed to be involved with

LFABP and IFABP in intestinal lipid metabolism

It is unusual that one cell type expresses proteins with identical functions; therefore, it is generally believed that LFABP and IFABP have different roles in intestinal lipid metabolism. In the intestine, the hydrolytic products of dietary lipids from the lumen enter the enterocyte from the lumen across the apical side of the cell, while endogenous lipids present in the bloodstream are delivered across the basolateral side [71]. The entry site into the enterocyte markedly impacts the metabolic

LFABP−/− mice

Two laboratories have independently generated individual lines of whole body LFABP-null mice on the C57BL/6 background [61], [82]. Martin et al. published their first report on the LFABP−/− mouse in 2003, in which there was complete deletion of all four exons of the LFABP gene along with the promoter region. These mice were backcrossed six times to the C57BL/6N mouse strain [82]. Newberry et al. also published a report in 2003 in which green fluorescent protein was “knocked in” to exons 1 and 2

IFABP−/− mice

One line of IFABP−/− mice has been generated, which were backcrossed for six generations onto the C57BL/6J background by Vassileva et al. [62]. Male mice fed diets with 35 kcal% fat as coconut oil and 1.25% cholesterol had an increase in body weight relative to WT mice, and also developed fatty livers. By contrast, female mice gained less weight than WT and did not exhibit any changes in hepatic lipid accumulation [62]. It was further found that aged (30- to 40-week old) male IFABP−/− mice fed 41

Direct comparison between LFABP−/− and IFABP−/− mice

To further investigate and systematically address the individual functions of these proteins, Lagakos et al. conducted comparative studies using both LFABP- and IFABP-null mice. LFABP-null mice, which were initially generated by Martin et al. [82], were used. These mice, which as noted above had been backcrossed for six generations onto the C57BL/6N strain, were backcrossed for another six generations onto the C57BL/6J strain [44]. IFABP−/− mice were bred from those used originally by Vassileva

Summary and perspective

Perhaps surprisingly, deletion of either LFABP or IFABP does not result in dietary lipid malabsorption, even with chronic high-fat feeding. Furthermore, and more remarkably, preliminary studies of an LFABP/IFABP double-knockout mouse show no increase in fecal fat on a high-fat diet (AM Gajda and J Storch, unpublished results). Ablation of each of these genes results in changes in intestinal lipid metabolism, as shown schematically in Fig. 2. These changes, which are relatively modest,

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    ☆

    This work was supported, in whole or in part, by the National Institutes of Health Grant DK-38389 from NIDDK. This work was also supported by funds from the New Jersey Agricultural Experiment Station.

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