Fatty acid transport proteins: targeting FATP2 as a gatekeeper involved in the transport of exogenous fatty acids

Abstract

Summary The fatty acid transport proteins (FATP) are classified as members of the Solute Carrier 27 (Slc27) family of proteins based on their ability to function in the transport of exogenous fatty acids. These proteins, when localized to the plasma membrane or at intracellular membrane junctions with the endoplasmic reticulum, function as a gate in the regulated transport of fatty acids and thus represent a therapeutic target to delimit the acquisition of fatty acids that contribute to disease as in the case of fatty acid overload. To date, FATP1, FATP2, and FATP4 have been used as targets in the selection of small molecule inhibitors with the goal of treating insulin resistance and attenuating dietary absorption of fatty acids. Several studies targeting FATP1 and FATP4 were based on the intrinsic acyl CoA synthetase activity of these proteins and not on transport directly. While several classes of compounds were identified as potential inhibitors of fatty acid transport, in vivo studies using a mouse model failed to provide evidence these compounds were effective in blocking or attenuating fatty acid transport. Studies targeting FATP2 employed a naturally occurring splice variant, FATP2b, which lacks intrinsic acyl CoA synthetase due to the deletion of exon 3, yet is fully functional in fatty acid transport. These studies identified two compounds, 5′-bromo-5-phenyl-spiro[3H-1,3,4-thiadiazole-2,3′-indoline]-2′-one), now referred to as Lipofermata, and 2-benzyl-3-(4-chlorophenyl)-5-(4-nitrophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one, now called Grassofermata, that are effective fatty acid transport inhibitors both in vitro using a series of model cell lines and in vivo using a mouse model.

Effects of nutritional status and diet composition on fatty acid transporters expression in zebrafish (Danio rerio)

“…Although the functions of these genes remain unknown in fish, genetic studies targeting FATP2, FATP4 and CD36 in mice have confirmed their function as fatty acid transporters in the liver and intestine (Anderson & Stahl, ; Pepino, Kuda, Samovski, & Abumrad, ). Evidences indicate that FATP2, FATP4 and CD36 play a role in intestinal lipid absorption in mammals (Anderson & Stahl, ; Black, Ahowesso, Montefusco, Saini, & Dirusso, ; Pepino et al, ). Furthermore, knockdown of mouse FATP2 is able to reverse established, high‐fat diet‐induced hepatosteatosis, and FATP2 plays a prominent role in hepatic fatty acid uptake (Falcon et al, ).…”

Intestinal Saturated Long-Chain Fatty Acid, Glucose and Fructose Transporters and Their Inhibition by Natural Plant Extracts in Caco-2 Cells

“…Studies tried to show the relevance of transporters in different models. The intestinal LCFA uptake of fatty acid transport protein 2 (FATP2)-knockout mice has not been observed, but selective FATP2 inhibitors, such as Lipofermata, show 80% attenuation of LCFA uptake across the gut [ 12 , 13 ]. A 48% decrease of FATP4 protein level leads to a 40% reduction of LCFA uptake in isolated primary enterocytes of mice, whereas no change of lipid uptake has been detected in vivo.…”

“…The LCFA transporter with the highest incidence in the intestinal system is still debated. The most represented opinion supported FATP4 [ 62 , 64 , 65 , 70 ], but since there was no effect of potential inhibitors in vivo, Black et al proposed FATP2 as a major intestinal LCFA transporter recently [ 13 ]. However, the ineffective in vivo studies of FATP4 inhibitors could relate to the inactivation of the inhibitors by the gut microbiome and/or to the large capacity of the small intestine regarding fat absorption [ 71 ].…”

“…VLACS forms fatty acid-CoA derivatives and therefore is able to improve the fatty acid transport due to stimulation of a concentration gradient [ 54 ], as shown in Figure 3 . The hypothesis of vectorial acylation as a requirement for the metabolism of LCFAs was first put forward by Overath et al 1969, when they started experiments with Escherichia coli (Migula, 1895), Castellani and Chalmers, 1919 [ 13 ]. The exact mechanism of protein-mediated LCFA trafficking into the cell is still not clarified by now.…”

Genetics of body fat mass and related traits in a pig population selected for leanness

“…Genetic variations in the porcine SLC26A6 gene are related to divergent lipid metabolism processes 35 . Although little is known about the role of SLC26A6 in the context of obesity, members of the fatty acid transport proteins are widely discussed as regulators of energy homeostasis, exogenous fatty acid uptake, and thermogenesis 36 .…”