title: EP 80317, a CD36 selective ligand, promotes reverse cholesterol transport in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  The CD36 selective ligand, EP 80317, features potent anti-atherosclerotic and hypocholesterolemic effects that are associated with an increase in macrophage cholesterol efflux through the activation of the peroxisome proliferator-activated receptor γ-liver X receptor α (LXRα)-ATP-binding cassette (ABC) transporter pathway. Cholesterol efflux is the first step of reverse cholesterol transport (RCT). However, whether EP 80317 exerts its hypocholesterolemic and anti-atherosclerotic activity through RCT in vivo has yet to be determined. In the present study, we investigated the effects of EP 80317 on RCT, in particular on macrophage-to-feces RCT and the expression of selected genes associated with hepatic cholesterol metabolism and intestinal cholesterol transport.
  
  
  RESULTS
  Reverse cholesterol transport was assessed following the intraperitoneal injection of [(3)H]-cholesterol-labelled J774 macrophages to hypercholesterolemic apoE- and apoE/CD36 double-deficient mice that had been treated for 12 weeks with EP 80317. Forty-eight hours after the administration of [(3)H]-cholesterol-labelled cells, blood, liver, intestines and feces were harvested. The radioactivity recovered in the feces (cholesterol and bile acid combined) was significantly increased by 311% (P = 0.0259) in EP 80317-treated mice compared with that found in vehicle-treated mice despite no significant change in [(3)H]-tracer recovery in plasma between groups. Whereas the mRNA levels of LXRα in the gut were significantly upregulated, mRNA and protein levels of the Niemann-Pick C1-like 1 protein (NPC1L1) transporter, a LXRα target which regulates intestinal cholesterol absorption, were downregulated in EP 80317-treated mice. In contrast, neither mRNA nor protein levels of investigated transporters and receptors were modulated in the small intestine of double-deficient mice, nor was the fecal recovery of radioactivity. No change was observed in targeted genes in liver of either apoE- or apoE/CD36 double-deficient mice after a chronic treatment with EP 80317.
  
  
  CONCLUSIONS
  This study shows that EP 80317 elicits macrophage-to-feces reverse cholesterol transport in a manner dependent on CD36 expression. This effect is associated with the upregulation of LXRα and the downregulation of NPC1L1 expression.
authors.affiliation: Faculté de pharmacie, Université de Montréal, QC, Canada.
authors.forename: Kim
authors.initials: K
authors.lastname: Bujold
authors.forename: Katia
authors.initials: K
authors.lastname: Mellal
authors.forename: Karina F
authors.initials: KF
authors.lastname: Zoccal
authors.forename: David
authors.initials: D
authors.lastname: Rhainds
authors.forename: Louise
authors.initials: L
authors.lastname: Brissette
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Sylvie
authors.initials: S
authors.lastname: Marleau
authors.forename: Huy
authors.initials: H
authors.lastname: Ong
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism*; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D007408:Intestinal Absorption / Q000187:drug effects* / Q000502:physiology; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009284:Naphthols; D009842:Oligopeptides / Q000494:pharmacology*; D057093:Orphan Nuclear Receptors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014227:Triazines
chemical_list: C409762:2-(3-aminophenol)-6-(4-amino-1-naphthol)-4-chloro-triazine; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D018955:CD36 Antigens; C468852:EP80317; D008074:Lipoproteins; D000071518:Liver X Receptors; D026901:Membrane Transport Proteins; D009284:Naphthols; C482445:Npc1l1 protein, mouse; C000605214:Nr1h3 protein, mouse; D009842:Oligopeptides; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D014227:Triazines; D002784:Cholesterol
keywords: ABCG5; ABCG8; CD36; NPC1L1; Reverse cholesterol transport