title: Different roles of liver X receptor alpha and beta in lipid metabolism: effects of an alpha-selective and a dual agonist in mice deficient in each subtype.
abstract: Liver X receptor (LXR) alpha and LXRbeta are closely related nuclear receptors that respond to elevated levels of intracellular cholesterol by enhancing transcription of genes that control cholesterol efflux and fatty acid biosynthesis. The consequences of inactivation of either LXR isoform have been thoroughly studied, as have the effects of simultaneous activation of both LXRalpha and LXRbeta by synthetic compounds. We here describe the effects of selective activation of LXRalpha or LXRbeta on lipid metabolism. This was accomplished by treating mice genetically deficient in either LXRalpha or LXRbeta with an agonist with equal potency for both isoforms (Compound B) or a synthetic agonist selective for LXRalpha (Compound A). We also determined the effect of these agonists on gene expression and cholesterol efflux in peritoneal macrophages derived from wild-type and knockout mice. Both compounds raised HDL-cholesterol and increased liver triglycerides in wild-type mice; in contrast, in mice deficient in LXRalpha, Compound B increased HDL-cholesterol but did not cause hepatic steatosis. Compound B induced ATP-binding cassette transporter (ABC) A1 expression and stimulated cholesterol efflux in macrophages from both LXRalpha and LXRbeta-deficient mice. Our data lend further experimental support to the hypothesis that LXRbeta-selective agonists may raise HDL-cholesterol and stimulate macrophage cholesterol efflux without causing liver triglyceride accumulation.
authors.affiliation: Department of Cardiovascular Diseases, Merck Research Laboratories, Merck & Co., Inc., RY80W-250, P.O. Box 2000, Rahway, NJ 07065, United States. erik_lund@merck.com
authors.forename: Erik G
authors.initials: EG
authors.lastname: Lund
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: Alan D
authors.initials: AD
authors.lastname: Adams
authors.forename: My-Hanh N
authors.initials: MH
authors.lastname: Lam
authors.forename: Charlotte A
authors.initials: CA
authors.lastname: Burton
authors.forename: Jayne
authors.initials: J
authors.lastname: Chin
authors.forename: Qiu
authors.initials: Q
authors.lastname: Guo
authors.forename: Shaei
authors.initials: S
authors.lastname: Huang
authors.forename: Melanie
authors.initials: M
authors.lastname: Latham
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Lopez
authors.forename: John G
authors.initials: JG
authors.lastname: Menke
authors.forename: Denise P
authors.initials: DP
authors.lastname: Milot
authors.forename: Lyndon J
authors.initials: LJ
authors.lastname: Mitnaul
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Rex-Rabe
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Rosa
authors.forename: Jenny Y
authors.initials: JY
authors.lastname: Tian
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Wright
authors.forename: Carl P
authors.initials: CP
authors.lastname: Sparrow
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D000242:Cyclic AMP / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D007555:Isoxazoles / Q000494:pharmacology; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D057093:Orphan Nuclear Receptors; D010671:Phenylurea Compounds / Q000494:pharmacology; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: C508985:(5-(methyl(3-((7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl)oxy)propyl)amino)pyrazin-2-yl)acetic acid; C508984:4-(((methyl(3-((7-propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl)oxy)propyl)amino)carbonyl)amino)benzoic acid; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D008076:Cholesterol, HDL; D004268:DNA-Binding Proteins; D007555:Isoxazoles; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D010671:Phenylurea Compounds; D020033:Protein Isoforms; D011719:Pyrazines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D015124:8-Bromo Cyclic Adenosine Monophosphate; D002784:Cholesterol; D000242:Cyclic AMP