Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs

Abstract

Fatty acid binding proteins (FABPs) act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs). PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L-) FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD) of PPARα. This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPARαLBD. The role of L-FABP in the delivery of ligands directly to PPARα via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed.

Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease

“…Functional PPREs were identified within the promoter of the intracellular lipid trafficking L-Fabp [54]. Direct protein-protein interaction were reported between PPARa and L-FABP, suggesting that L-FABP may channel PPARa ligands to the receptor [55,56]. Consistently, a positive correlation between L-FABP protein and PPRE-driven gene transcription was observed in human hepatoma HepG2 cells, treated with PPARa agonists [57].…”

Fatty Acid Binding Proteins Expressed at the Human Blood–Brain Barrier Bind Drugs in an Isoform-Specific Manner

“…We therefore used ANS as a probe and assessed whether hFABP3, 4 and 5 could bind to a panel of drugs using a fluorescence-displacement assay. ANS has been previously used to evaluate drug binding to both rat and human FABP1 and FABP2 (17,19,40). The K d values of ANS to these FABPs have been reported to be in the low micromolar range (20,29,41).…”

Fatty acid binding proteins have the potential to channel dietary fatty acids into enterocyte nuclei

“…It was demonstrated, using cell cultures, that FABPs may channel unesterifi ed FAs and other lipophilic ligands into nuclei, potentially targeting them to transcription factors, and initiate nuclear receptor transcriptional activity ( 11,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33). To our knowledge, no in vivo data are currently available to support the hypothesis that exogenous FAs enter cell nuclei via their binding to FABPs.…”