Fatty acid-binding proteins 1 and 2 differentially modulate the activation of peroxisome proliferator-activated receptor alpha in a ligand-selective manner

Maria Lourdes Regina Hughes, Bonan Liu, Michelle Louise Halls, Kylie Michelle Wagstaff, Rahul Patil, Tony Velkov, David Andrew Jans, Nigel William Bunnett, Martin Scanlon, Christopher John Porter

Research output: Contribution to journalArticleResearchpeer-review

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) a. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARa activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARa. 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 PPARa 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.
Original languageEnglish
Pages (from-to)13895 - 13906
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number22
DOIs
Publication statusPublished - 2015

Cite this

@article{dec90d0db0854971aa9792a4d2b96e73,
title = "Fatty acid-binding proteins 1 and 2 differentially modulate the activation of peroxisome proliferator-activated receptor alpha 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) a. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARa activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARa. 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 PPARa 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.",
author = "Hughes, {Maria Lourdes Regina} and Bonan Liu and Halls, {Michelle Louise} and Wagstaff, {Kylie Michelle} and Rahul Patil and Tony Velkov and Jans, {David Andrew} and Bunnett, {Nigel William} and Martin Scanlon and Porter, {Christopher John}",
year = "2015",
doi = "10.1074/jbc.M114.605998",
language = "English",
volume = "290",
pages = "13895 -- 13906",
journal = "Journal of Biological Chemistry",
issn = "1083-351X",
publisher = "American Society for Biochemistry and Molecular Biology",
number = "22",

}

Fatty acid-binding proteins 1 and 2 differentially modulate the activation of peroxisome proliferator-activated receptor alpha in a ligand-selective manner. / Hughes, Maria Lourdes Regina; Liu, Bonan; Halls, Michelle Louise; Wagstaff, Kylie Michelle; Patil, Rahul; Velkov, Tony; Jans, David Andrew; Bunnett, Nigel William; Scanlon, Martin; Porter, Christopher John.

In: Journal of Biological Chemistry, Vol. 290, No. 22, 2015, p. 13895 - 13906.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Fatty acid-binding proteins 1 and 2 differentially modulate the activation of peroxisome proliferator-activated receptor alpha in a ligand-selective manner

AU - Hughes, Maria Lourdes Regina

AU - Liu, Bonan

AU - Halls, Michelle Louise

AU - Wagstaff, Kylie Michelle

AU - Patil, Rahul

AU - Velkov, Tony

AU - Jans, David Andrew

AU - Bunnett, Nigel William

AU - Scanlon, Martin

AU - Porter, Christopher John

PY - 2015

Y1 - 2015

N2 - 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) a. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARa activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARa. 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 PPARa 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.

AB - 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) a. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARa activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARa. 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 PPARa 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.

UR - http://www.jbc.org.ezproxy.lib.monash.edu.au/content/290/22/13895.full.pdf+html

U2 - 10.1074/jbc.M114.605998

DO - 10.1074/jbc.M114.605998

M3 - Article

VL - 290

SP - 13895

EP - 13906

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 1083-351X

IS - 22

ER -