title: Fatty Acid-binding Proteins 1 and 2 Differentially Modulate the Activation of Peroxisome Proliferator-activated Receptor α in a Ligand-selective Manner.
abstract: Nuclear hormone receptors (NHRs) regulate the expression of proteins that control aspects of reproduction, development and metabolism, and are major therapeutic targets. However, NHRs are ubiquitous and participate in multiple physiological processes. Drugs that act at NHRs are therefore commonly restricted by toxicity, often at nontarget organs. For endogenous NHR ligands, intracellular lipid-binding proteins, including the fatty acid-binding proteins (FABPs), can chaperone ligands to the nucleus and promote NHR activation. Drugs also bind FABPs, raising the possibility that FABPs similarly regulate drug activity at the NHRs. Here, we investigate the ability of FABP1 and FABP2 (intracellular lipid-binding proteins that are highly expressed in tissues involved in lipid metabolism, including the liver and intestine) to influence drug-mediated activation of the lipid regulator peroxisome proliferator-activated receptor (PPAR) α. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARα activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARα. Nuclear accumulation of FABP on drug binding is driven largely by reduced nuclear egress rather than an increased rate of nuclear entry. Importin binding assays indicate that nuclear access occurs via an importin-independent mechanism. Together, the data suggest that specific drug-FABP complexes can interact with PPARα to effect nuclear accumulation of FABP and NHR activation. Because FABPs are expressed in a regionally selective manner, this may provide a means to tailor the patterns of NHR drug activation in a tissue-specific manner.
authors.affiliation: From Drug Delivery, Disposition and Dynamics.
authors.forename: Maria L R
authors.initials: ML
authors.lastname: Hughes
authors.affiliation: From Drug Delivery, Disposition and Dynamics.
authors.forename: Bonan
authors.initials: B
authors.lastname: Liu
authors.affiliation: Drug Discovery Biology.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Halls
authors.affiliation: the Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria 3800, and.
authors.forename: Kylie M
authors.initials: KM
authors.lastname: Wagstaff
authors.affiliation: Medicinal Chemistry.
authors.forename: Rahul
authors.initials: R
authors.lastname: Patil
authors.affiliation: From Drug Delivery, Disposition and Dynamics.
authors.forename: Tony
authors.initials: T
authors.lastname: Velkov
authors.affiliation: the Department of Biochemistry and Molecular Biology, Faculty of Medicine, Nursing and Health Sciences, Monash University, Victoria 3800, and.
authors.forename: David A
authors.initials: DA
authors.lastname: Jans
authors.affiliation: Drug Discovery Biology, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, the Department of Pharmacology, University of Melbourne, Victoria 3010, Australia nigel.bunnett@monash.edu.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Bunnett
authors.affiliation: Medicinal Chemistry, martin.scanlon@monash.edu.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Scanlon
authors.affiliation: From Drug Delivery, Disposition and Dynamics, ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria, 3052, chris.porter@monash.edu.
authors.forename: Christopher J H
authors.identifier: http://orcid.org/0000-0003-3474-7551
authors.initials: CJ
authors.lastname: Porter
mesh_terms: D000818:Animals; D001692:Biological Transport; D019556:COS Cells; D002151:Calorimetry; D002467:Cell Nucleus / Q000378:metabolism; D002522:Chlorocebus aethiops; D016503:Drug Delivery Systems; D015195:Drug Design; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism*; D031541:Fluorescence Resonance Energy Transfer; D005786:Gene Expression Regulation; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D008024:Ligands; D008055:Lipids / Q000737:chemistry; D047493:PPAR alpha / Q000378:metabolism*; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D025941:Protein Interaction Mapping
chemical_list: C493319:FABP1 protein, human; C493404:FABP2 protein, human; D050556:Fatty Acid-Binding Proteins; D028884:Karyopherins; D008024:Ligands; D008055:Lipids; D047493:PPAR alpha
keywords: drug delivery; drug discovery; drug transport; intracellular transport; lipid-binding protein; peroxisome proliferator-activated receptor (PPAR)
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