title: Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice.
abstract: OBJECTIVE
  The goal of this study was to determine the impact of the nuclear receptor constitutive androstane receptor (CAR) on lipoprotein metabolism and atherosclerosis in hyperlipidemic mice.
  
  
  RESULTS
  Low-density lipoprotein receptor-deficient (Ldlr(-/-)) and apolipoprotein E-deficient (ApoE(-/-)) mice fed a Western-type diet were treated weekly with the Car agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or the vehicle only for 8 weeks. In Ldlr(-/-) mice, treatment with TCPOBOP induced a decrease in plasma triglyceride and intermediate-density lipoprotein/low-density lipoprotein cholesterol levels (≈30% decrease in both cases after 2 months, P<0.01). These mice also showed a significant reduction in the production of very-low-density lipoproteins associated with a decrease in hepatic triglyceride content and the repression of several genes involved in lipogenesis. TCPOBOP treatment also induced a marked increase in the very-low-density lipoprotein receptor in the liver, which probably contributed to the decrease in intermediate-density lipoprotein/low-density lipoprotein levels. Atherosclerotic lesions in the aortic valves of TCPOBOP-treated Ldlr(-/-) mice were also reduced (-60%, P<0.001). In ApoE(-/-) mice, which lack the physiological apoE ligand for the very-low-density lipoprotein receptor, the effect of TCPOBOP on plasma cholesterol levels and the development of atherosclerotic lesions was markedly attenuated.
  
  
  CONCLUSIONS
  CAR is a potential target in the prevention and treatment of hypercholesterolemia and atherosclerosis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U, Faculté de Médecine, Dijon, France.
authors.forename: Anne-Laure
authors.initials: AL
authors.lastname: Sberna
authors.forename: Mahfoud
authors.initials: M
authors.lastname: Assem
authors.forename: Rui
authors.initials: R
authors.lastname: Xiao
authors.forename: Steve
authors.initials: S
authors.lastname: Ayers
authors.forename: Thomas
authors.initials: T
authors.lastname: Gautier
authors.forename: Boris
authors.initials: B
authors.lastname: Guiu
authors.forename: Valérie
authors.initials: V
authors.lastname: Deckert
authors.forename: Angélique
authors.initials: A
authors.lastname: Chevriaux
authors.forename: Jacques
authors.initials: J
authors.lastname: Grober
authors.forename: Naig
authors.initials: N
authors.lastname: Le Guern
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Pais de Barros
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.forename: Laurent
authors.initials: L
authors.lastname: Lagrost
authors.forename: David
authors.initials: D
authors.lastname: Masson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000097:blood*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D017930:Genes, Reporter; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050155:Lipogenesis / Q000235:genetics; D008074:Lipoproteins / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011725:Pyridines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements; D013997:Time Factors; D014162:Transfection; D014280:Triglycerides / Q000097:blood
chemical_list: C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D001057:Apolipoproteins E; D008078:Cholesterol, LDL; D000090702:Constitutive Androstane Receptor; D008074:Lipoproteins; D008079:Lipoproteins, VLDL; D011725:Pyridines; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014280:Triglycerides; C036053:VLDL receptor; C030104:lipoprotein cholesterol; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D002784:Cholesterol