title: Liver X Receptor Regulates Triglyceride Absorption Through Intestinal Down-regulation of Scavenger Receptor Class B, Type 1.
abstract: OBJECTIVE
  Reducing postprandial triglyceridemia may be a promising strategy to lower the risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors [LXRs]) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption.
  
  
  METHODS
  C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured the production of chylomicrons and localized SR-B1 by immunohistochemistry. Mechanisms of postprandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists.
  
  
  RESULTS
  In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipidic-micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool toward secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves microRNAs.
  
  
  CONCLUSIONS
  In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces the production of chylomicrons by a mechanism dependent on the apical localization of SR-B1.
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Briand
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Touche
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Colin
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gemma
authors.initials: G
authors.lastname: Brufau
authors.affiliation: Madrid Institute for Advanced Studies (IMDEA) Food Institute, Laboratory of Disorders of Lipid Metabolism and Molecular Nutrition, Campus de Excelencia Internacional (CEI), Universidad Autónoma de Madrid (UAM), Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Davalos
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marleen
authors.initials: M
authors.lastname: Schonewille
authors.affiliation: National Research Cancer Center, Giovanni Paolo II, and University of Bari, Bari, Italy.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Bovenga
authors.affiliation: Institut National de la Santé et de la Recherche Médicale (INSERM), UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cit, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigatión Sanitaria (IRYCIS), Madrid, Spain.
authors.forename: Véronique
authors.initials: V
authors.lastname: Carrière
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Jan Freark
authors.initials: JF
authors.lastname: de Boer
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Dugardin
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC), UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France; Université Paris Descartes, Sorbonne Paris Cit, UMR_S 1138, Centre de Recherche des Cordeliers, Paris, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Riveau
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Clavey
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Tailleux
authors.affiliation: National Research Cancer Center, Giovanni Paolo II, and University of Bari, Bari, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Moschetta
authors.affiliation: Servicio de Bioquímica-Investigación, Hospital Ramón y Cajal, Instituto Ramón y Cajal de Investigatión Sanitaria (IRYCIS), Madrid, Spain; Centro de Investigatión Biomedica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición, Instituto de Salud Carlos III, Spain.
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Lasunción
authors.affiliation: Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France. Electronic address: bart.staels@pasteur-lille.fr.
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.affiliation: University Lille, Inserm, Centre Hospitalier Universitaire (CHU) de Lille, Institut Pasteur de Lille, U1011-European Genomic Institute for Diabetes, Lille, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lestavel
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D018938:Caco-2 Cells; D002791:Cholesterol, Dietary / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000172:deficiency / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007583:Jejunum / Q000187:drug effects / Q000378:metabolism*; D000071518:Liver X Receptors; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic; D014162:Transfection; D014280:Triglycerides / Q000378:metabolism*; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001565:Benzoates; D001596:Benzylamines; D002791:Cholesterol, Dietary; D002914:Chylomicrons; D053487:DEAD-box RNA Helicases; D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D035683:MicroRNAs; D057093:Orphan Nuclear Receptors; D043244:Ribonuclease III; D051122:Scavenger Receptors, Class B; D013449:Sulfonamides; D014280:Triglycerides; C569471:APOB protein, human; C415826:Apob protein, mouse; C473027:GW 3965; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C509781:Dicer1 protein, mouse
keywords: Fat Absorption; Hypertriglyceridemia; Lipid-Sensing; Triglyceride-Rich Lipoproteins