title: Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers.
abstract: BACKGROUND
  Detoxification in the liver involves activation of nuclear receptors, such as the constitutive androstane receptor (CAR), which regulate downstream genes of xenobiotic metabolism. Frequently, the metabolism of endobiotics is also modulated, resulting in potentially harmful effects. We therefore used 1,4-Bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) to study the effect of CAR activation on mouse hepatic transcriptome and lipid metabolome under conditions of diet-induced hyperlipidemia.
  
  
  RESULTS
  Using gene expression profiling with a dedicated microarray, we show that xenobiotic metabolism, PPARalpha and adipocytokine signaling, and steroid synthesis are the pathways most affected by TCPOBOP in normal and hyperlipidemic mice. TCPOBOP-induced CAR activation prevented the increased hepatic and serum cholesterol caused by feeding mice a diet containing 1% cholesterol. We show that this is due to increased bile acid metabolism and up-regulated removal of LDL, even though TCPOBOP increased cholesterol synthesis under conditions of hyperlipidemia. Up-regulation of cholesterol synthesis was not accompanied by an increase in mature SREBP2 protein. As determined by studies in CAR -/- mice, up-regulation of cholesterol synthesis is however CAR-dependent; and no obvious CAR binding sites were detected in promoters of cholesterogenic genes. TCPOBOP also affected serum glucose and triglyceride levels and other metabolic processes in the liver, irrespective of the diet.
  
  
  CONCLUSIONS
  Our data show that CAR activation modulates hepatic metabolism by lowering cholesterol and glucose levels, through effects on PPARalpha and adiponectin signaling pathways, and by compromising liver adaptations to hyperlipidemia.
authors.affiliation: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia. tadeja.rezen@mf.uni-lj.si
authors.forename: Tadeja
authors.initials: T
authors.lastname: Rezen
authors.forename: Viola
authors.initials: V
authors.lastname: Tamasi
authors.forename: Anita
authors.initials: A
authors.lastname: Lövgren-Sandblom
authors.forename: Ingemar
authors.initials: I
authors.lastname: Björkhem
authors.forename: Urs A
authors.initials: UA
authors.lastname: Meyer
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
mesh_terms: D052242:Adiponectin / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D047493:PPAR alpha / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D000090702:Constitutive Androstane Receptor; D047493:PPAR alpha; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014280:Triglycerides; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D002784:Cholesterol
references.citation: Clin Sci Mol Med. 1976 May;50(5):349-53
references.pmid: 6182
references.citation: Annu Rev Cell Dev Biol. 2000;16:459-81
references.pmid: 11031244
references.citation: Mol Endocrinol. 2005 Jun;19(6):1646-53
references.pmid: 15831521
references.citation: Gut. 2007 Apr;56(4):565-74
references.pmid: 16950832
references.citation: Metabolism. 1994 Mar;43(3):348-56
references.pmid: 8139483
references.citation: Hepatology. 2005 Aug;42(2):420-30
references.pmid: 15986414
references.citation: J Clin Invest. 2002 May;109(9):1125-31
references.pmid: 11994399
references.citation: J Nutr Biochem. 2007 Mar;18(3):184-95
references.pmid: 17296492
references.citation: Curr Drug Metab. 2005 Aug;6(4):329-39
references.pmid: 16101572
references.citation: Mol Pharmacol. 2002 Jan;61(1):1-6
references.pmid: 11752199
references.citation: Biol Chem. 2008 Oct;389(10):1313-8
references.pmid: 18713018
references.citation: Mol Cell Biol. 2004 Sep;24(18):7931-40
references.pmid: 15340055
references.citation: BMC Genomics. 2008 Feb 11;9:76
references.pmid: 18261244
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 2;101(44):15597-602
references.pmid: 15496471
references.citation: Biochem Biophys Res Commun. 2008 Nov 7;376(1):206-10
references.pmid: 18775413
references.citation: Mol Endocrinol. 2002 Jun;16(6):1269-79
references.pmid: 12040014
references.citation: Genome Biol. 2007;8(1):R3
references.pmid: 17204154
references.citation: J Lipid Res. 2009 Mar;50(3):439-445
references.pmid: 18941143
references.citation: J Clin Invest. 2006 Jul;116(7):1784-92
references.pmid: 16823476
references.citation: Hepatology. 2008 Oct;48(4):1302-11
references.pmid: 18798339
references.citation: Curr Drug Metab. 2008 Sep;9(7):614-21
references.pmid: 18781913
references.citation: J Biol Chem. 2006 May 26;281(21):14537-46
references.pmid: 16492670
references.citation: Acta Neurol Scand. 1991 Apr;83(4):250-3
references.pmid: 2048399
references.citation: Pharmacol Ther. 1999 Apr;82(1):63-70
references.pmid: 10341357
references.citation: Gut. 2005 Jan;54(1):117-21
references.pmid: 15591515
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: Epilepsia. 1992 Sep-Oct;33(5):932-5
references.pmid: 1396438
references.citation: Trends Endocrinol Metab. 2006 Sep;17(7):284-90
references.pmid: 16870465
references.citation: Mol Pharmacol. 2008 Apr;73(4):1282-9
references.pmid: 18187584
references.citation: Arch Toxicol. 2004 Aug;78(8):435-42
references.pmid: 15107969
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):2063-8
references.pmid: 15684063
references.citation: J Lipid Res. 1987 Oct;28(10):1137-43
references.pmid: 3681138
references.citation: J Biol Chem. 2003 Nov 14;278(46):45062-71
references.pmid: 12923173
references.citation: Diabetes. 1985 Sep;34(9):911-6
references.pmid: 3896900
references.citation: J Lipid Res. 2008 Aug;49(8):1682-91
references.pmid: 18441373