title: Fatty Acid Transport Proteins: Targeting FATP2 as a Gatekeeper Involved in the Transport of Exogenous Fatty Acids.
abstract: 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 vivostudies 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 bothin vitrousing a series of model cell lines andin vivousing a mouse model.
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, NE.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Black
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, NE.
authors.forename: Constance
authors.initials: C
authors.lastname: Ahowesso
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, NE.
authors.forename: David
authors.initials: D
authors.lastname: Montefusco
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, NE.
authors.forename: Nipun
authors.initials: N
authors.lastname: Saini
authors.affiliation: Department of Biochemistry, University of Nebraska, Lincoln, NE.
authors.forename: Concetta C
authors.initials: CC
authors.lastname: DiRusso