title: Synthetic LXR agonist attenuates plaque formation in apoE-/- mice without inducing liver steatosis and hypertriglyceridemia.
abstract: Liver X receptors (LXRs) are important regulators of cholesterol and lipid metabolism. LXR agonists have been shown to limit the cellular cholesterol content by inducing reverse cholesterol transport, increasing bile acid production, and inhibiting intestinal cholesterol absorption. Most of them, however, also increase lipogenesis via sterol regulatory element-binding protein-1c (SREBP1c) and carbohydrate response element-binding protein activation resulting in hypertriglyceridemia and liver steatosis. We report on the antiatherogenic properties of the steroidal liver X receptor agonist N,N-dimethyl-3beta-hydroxy-cholenamide (DMHCA) in apolipoprotein E (apoE)-deficient mice. Long-term administration of DMHCA (11 weeks) significantly reduced lesion formation in male and female apoE-null mice. Notably, DMHCA neither increased hepatic triglyceride (TG) levels in male nor female apoE-deficient mice. ATP binding cassette transporter A1 and G1 and cholesterol 7alpha-hydroxylase mRNA abundances were increased, whereas SREBP1c mRNA expression was unchanged in liver, and even decreased in macrophages and intestine. Short-term treatment revealed even higher changes on mRNA regulation. Our data provide evidence that DMHCA is a strong candidate as therapeutic agent for the treatment or prevention of atherosclerosis, circumventing the negative side effects of other LXR agonists.
authors.affiliation: Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, Harrachgasse 21/3, 8010 Graz, Austria.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Kratzer
authors.forename: Marlene
authors.initials: M
authors.lastname: Buchebner
authors.forename: Thomas
authors.initials: T
authors.lastname: Pfeifer
authors.forename: Tatjana M
authors.initials: TM
authors.lastname: Becker
authors.forename: Georg
authors.initials: G
authors.lastname: Uray
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.forename: Shinobu
authors.initials: S
authors.lastname: Miyazaki-Anzai
authors.forename: Birgit
authors.initials: B
authors.lastname: Ebner
authors.forename: Prakash G
authors.initials: PG
authors.lastname: Chandak
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Kadam
authors.forename: Emine
authors.initials: E
authors.lastname: Calayir
authors.forename: Nora
authors.initials: N
authors.lastname: Rathke
authors.forename: Helmut
authors.initials: H
authors.lastname: Ahammer
authors.forename: Branislav
authors.initials: B
authors.lastname: Radovic
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
authors.forename: Guenter
authors.initials: G
authors.lastname: Fauler
authors.forename: Moshe
authors.initials: M
authors.lastname: Levi
authors.forename: Sanja
authors.initials: S
authors.lastname: Levak-Frank
authors.forename: Gerhard M
authors.initials: GM
authors.lastname: Kostner
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D002793:Cholic Acids / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D005234:Fatty Liver / Q000139:chemically induced; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D015228:Hypertriglyceridemia / Q000139:chemically induced; D000071518:Liver X Receptors; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001057:Apolipoproteins E; D002793:Cholic Acids; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C413890:N,N-dimethyl-3-hydroxy-5-cholenamide; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1