title: A novel potent synthetic steroidal liver X receptor agonist lowers plasma cholesterol and triglycerides and reduces atherosclerosis in LDLR(-/-) mice.
abstract: OBJECTIVE
  Potent synthetic nonsteroidal liver X receptor (LXR) agonists like T0901317 induce triglyceridaemia and fatty liver, effects not observed with some natural and synthetic steroidal, relatively weak agonists of LXR. To determine if potency is responsible for the lack of side effects with some steroidal agonists, we investigated the in vivo effects of a novel steroidal LXR agonist, ATI-111, that is more potent than T0901317.
  
  
  METHODS
  Eight week old male LDLR(-/-) mice fed an atherogenic diet were orally treated with vehicle or ATI-111 at 3 and 5 mg·kg(-1) ·day(-1) for 8 weeks, and effects on plasma and liver lipid levels, expression of genes involved in lipid metabolism and on atherogenesis were analysed.
  
  
  RESULTS
  ATI-111 increased the expression of genes involved in lipid transport, such as ABCA1, ABCG1 and ABCG5/G8, in intestine and macrophages; decreased ABCG1, apoE; and slightly increased ABCA1 and ABCG5/G8 expression in liver. ATI-111 markedly increased sterol regulatory element-binding protein (SREBP)-1c mRNA in some tissues, whereas acetyl-coenzyme A carboxylase and fatty acid synthase expression was unaffected or only slightly increased in intestine and liver. ATI-111 inhibited the conversion of SREBP-1c precursor form to its active form. Compared with vehicle-treated mice, the levels of hepatic lipids and liver-secreted nascent lipoproteins were not altered, while a significant decrease in plasma cholesterol and triglyceride levels was observed in ATI-111-treated mice. ATI-111 significantly inhibited atherogenesis in three separate vascular sites.
  
  
  CONCLUSIONS
  ATI-111 is a promising candidate for further development as a treatment of certain vascular diseases as it lacks the significant side effects associated with nonsteroidal LXR agonists, the induction of fatty liver and hypertriglyceridaemia.
authors.affiliation: Ben May Department for Cancer Research, University of Chicago, Chicago, IL, USA.
authors.forename: Dacheng
authors.initials: D
authors.lastname: Peng
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hiipakka
authors.forename: Jing-Tian
authors.initials: JT
authors.lastname: Xie
authors.forename: Qing
authors.initials: Q
authors.lastname: Dai
authors.forename: John M
authors.initials: JM
authors.lastname: Kokontis
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Reardon
authors.forename: Godfrey S
authors.initials: GS
authors.lastname: Getz
authors.forename: Shutsung
authors.initials: S
authors.lastname: Liao
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000503:physiopathology; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006914:Hydroxysteroids / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000819:agonists*; D011973:Receptors, LDL / Q000235:genetics*; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: C559195:ATI-111 cpd; D006914:Hydroxysteroids; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D011973:Receptors, LDL; D014280:Triglycerides; D002784:Cholesterol