title: Low dose of the liver X receptor agonist, AZ876, reduces atherosclerosis in APOE*3Leiden mice without affecting liver or plasma triglyceride levels.
abstract: OBJECTIVE
  Liver X receptor (LXR) agonists are atheroprotective but often induce hypertriglyceridaemia and liver steatosis. We investigated the effect of a novel high-affinity LXR activator, AZ876, on plasma lipids, inflammation and atherosclerosis, and compared the effects with another LXR agonist, GW3965.
  
  
  METHODS
  APOE*3Leiden mice were fed an atherogenic diet alone or supplemented with either AZ876 (5 or 20µmol·kg(-1) ·day(-1) ) or GW3965 (17µmol·kg(-1) ·day(-1) ) for 20 weeks. Total cholesterol and triglyceride levels were measured using commercial kits. Plasma cytokines were determined by using bead-based multiplex suspension array kits with the Luminex technology. Atherosclerosis was assessed histochemically and lesion composition was assessed by immunohistochemical methods.
  
  
  RESULTS
  Low-dose AZ876 had no effect on plasma or liver lipids, whereas high-dose AZ876 increased plasma triglycerides (+110%) and reduced cholesterol (-16%) compared with controls. GW3965 increased plasma triglycerides (+70%). Low-dose AZ876 reduced lesion area (-47%); and high-dose AZ876 strongly decreased lesion area (-91%), lesion number (-59%) and severity. In either dose, AZ876 did not affect lesion composition. GW3965 reduced atherosclerosis and collagen content of lesions (-23%; P < 0.01). High-dose AZ876 and GW3965, but not low-dose AZ876, reduced inflammation as reflected by lower cytokine levels and vessel wall activation.
  
  
  CONCLUSIONS
  We have identified a novel LXR agonist that when given in a low dose inhibits the progression of atherosclerosis without inducing anti-inflammatory effects, liver steatosis or hypertriglyceridaemia. Therefore, the primary protective action of a low-dose AZ876 is likely to be an increased reverse cholesterol transport.
authors.affiliation: TNO BioSciences, Leiden, the Netherlands. jose.vanderhoorn@tno.nl
authors.forename: Jwa
authors.initials: J
authors.lastname: van der Hoorn
authors.forename: D
authors.initials: D
authors.lastname: Lindén
authors.forename: U
authors.initials: U
authors.lastname: Lindahl
authors.forename: Mea
authors.initials: M
authors.lastname: Bekkers
authors.forename: M
authors.initials: M
authors.lastname: Voskuilen
authors.forename: R
authors.initials: R
authors.lastname: Nilsson
authors.forename: J
authors.initials: J
authors.lastname: Oscarsson
authors.forename: El
authors.initials: E
authors.lastname: Lindstedt
authors.forename: Hmg
authors.initials: H
authors.lastname: Princen
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia / Q000139:chemically induced / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000096:biosynthesis / Q000235:genetics; D013844:Thiazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: C559287:AZ 876; D000814:Aniline Compounds; D053318:Apolipoprotein E3; D001565:Benzoates; D001596:Benzylamines; D016207:Cytokines; C473027:GW 3965; D008055:Lipids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013844:Thiazoles; D014280:Triglycerides; C052720:apolipoprotein E3 (Leidein); D002784:Cholesterol