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.
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.
Lund
Erik G
EG
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
Peterson
Laurence B
LB
Adams
Alan D
AD
Lam
My-Hanh N
MH
Burton
Charlotte A
CA
Chin
Jayne
J
Guo
Qiu
Q
Huang
Shaei
S
Latham
Melanie
M
Lopez
Jacqueline C
JC
Menke
John G
JG
Milot
Denise P
DP
Mitnaul
Lyndon J
LJ
Rex-Rabe
Sandra E
SE
Rosa
Raymond L
RL
Tian
Jenny Y
JY
Wright
Samuel D
SD
Sparrow
Carl P
CP
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
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