title: Transintestinal transport of the anti-inflammatory drug 4F and the modulation of transintestinal cholesterol efflux.
abstract: The site and mechanism of action of the apoA-I mimetic peptide 4F are incompletely understood. Transintestinal cholesterol efflux (TICE) is a process involved in the clearance of excess cholesterol from the body. While TICE is responsible for at least 30% of the clearance of neutral sterols from the circulation into the intestinal lumen, few pharmacological agents have been identified that modulate this pathway. We show first that circulating 4F selectively targets the small intestine (SI) and that it is predominantly transported into the intestinal lumen. This transport of 4F into the SI lumen is transintestinal in nature, and it is modulated by TICE. We also show that circulating 4F increases reverse cholesterol transport from macrophages and cholesterol efflux from lipoproteins via the TICE pathway. We identify the cause of this modulation of TICE either as 4F being a cholesterol acceptor with respect to enterocytes, from which 4F enhances cholesterol efflux, or as 4F being an intestinal chaperone with respect to TICE. Our results assign a novel role for 4F as a modulator of the TICE pathway and suggest that the anti-inflammatory functions of 4F may be a partial consequence of the codependent intestinal transport of both 4F and cholesterol.
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA Department of Medical and Molecular Pharmacology, University of California Los Angeles, Los Angeles, CA.
authors.forename: David
authors.initials: D
authors.lastname: Meriwether
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA Molecular Toxicology Interdepartmental Degree Program, University of California Los Angeles, Los Angeles, CA.
authors.forename: Dawoud
authors.initials: D
authors.lastname: Sulaiman
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Alan
authors.initials: A
authors.lastname: Wagner
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Victor
authors.initials: V
authors.lastname: Grijalva
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Izumi
authors.initials: I
authors.lastname: Kaji
authors.affiliation: Department of Medical and Molecular Pharmacology, University of California Los Angeles, Los Angeles, CA.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Williams
authors.affiliation: Department of Animal and Avian Sciences, University of Maryland, College Park, MD.
authors.forename: Liqing
authors.initials: L
authors.lastname: Yu
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Fogelman
authors.affiliation: Division of Laboratory Animal Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Carmen
authors.initials: C
authors.lastname: Volpe
authors.affiliation: Department of Medical and Molecular Pharmacology, University of California Los Angeles, Los Angeles, CA Department of Microbiology, Immunology and Molecular Genetics, University of California Los Angeles, Los Angeles, CA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Ishaiahu
authors.initials: I
authors.lastname: Shechter
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
authors.affiliation: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA Department of Medical and Molecular Pharmacology, University of California Los Angeles, Los Angeles, CA Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA sreddy@mednet.ucla.edu.
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001692:Biological Transport; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D007421:Intestine, Small / Q000378:metabolism; D008074:Lipoproteins / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; D008074:Lipoproteins; D010455:Peptides; C582295:apolipoprotein A-I mimetic peptide 4F; D002784:Cholesterol
keywords: apolipoprotein A-I mimetic peptides; atherosclerosis; cholesterol; reverse cholesterol transport