title: PPAR-α, a lipid-sensing transcription factor, regulates blood-brain barrier efflux transporter expression.
abstract: Lipid sensor peroxisome proliferator-activated receptor alpha (PPAR- α) is the master regulator of lipid metabolism. Dietary release of endogenous free fatty acids, fibrates, and certain persistent environmental pollutants, e.g. perfluoroalkyl fire-fighting foam components, are peroxisome proliferator-activated receptor alpha ligands. Here, we define a role for peroxisome proliferator-activated receptor alpha in regulating the expression of three ATP-driven drug efflux transporters at the rat and mouse blood-brain barriers: P-glycoprotein (Abcb1), breast cancer resistance protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2). Exposing isolated rat brain capillaries to linoleic acid, clofibrate, or PKAs increased the transport activity and protein expression of the three ABC transporters. These effects were blocked by the PPAR- α antagonist, GW6471. Dosing rats with 20 mg/kg or 200 mg/kg of clofibrate decreased the brain accumulation of the P-glycoprotein substrate, verapamil, by 50% (in situ brain perfusion; effects blocked by GW6471) and increased P-glycoprotein expression and activity in capillaries ex vivo. Fasting C57Bl/6 wild-type mice for 24 h increased both serum lipids and brain capillary P-glycoprotein transport activity. Fasting did not alter P-glycoprotein activity in PPAR- α knockout mice. These results indicate that hyperlipidemia, lipid-lowering fibrates and exposure to certain fire-fighting foam components activate blood-brain barrier peroxisome proliferator-activated receptor alpha, increase drug efflux transporter expression and reduce drug delivery to the brain.
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
authors.forename: Vijay R
authors.initials: VR
authors.lastname: More
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Campos
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Evans
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Oliver
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
authors.forename: Gary Ny
authors.initials: GN
authors.lastname: Chan
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Miller
authors.affiliation: Signal Transduction Laboratory, National Institute of Environmental Health Sciences (NIEHS), National Institute of Health, Research Triangle Park, NC, USA.
authors.forename: Ronald E
authors.initials: RE
authors.lastname: Cannon
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D017738:Alkanesulfonic Acids / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000098:blood supply; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002994:Clofibrate / Q000494:pharmacology; D005215:Fasting / Q000378:metabolism; D005466:Fluorocarbons / Q000494:pharmacology; D005786:Gene Expression Regulation; D019787:Linoleic Acid / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D017207:Rats, Sprague-Dawley; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; D017738:Alkanesulfonic Acids; D002994:Clofibrate; D005466:Fluorocarbons; D019787:Linoleic Acid; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010080:Oxazoles; D047493:PPAR alpha; D014443:Tyrosine; C449302:GW 6471; C076994:perfluorooctane sulfonic acid
keywords: Blood–brain barrier; P-glycoprotein; PPAR; fasting; fibrate