Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers

Tadeja Režen, V. Tamási, Anita Lövgren-Sandblom, Ingemar Björkhem, Urs A. Meyer, Damjana Rozman

Research output: Contribution to journalArticle

35 Citations (Scopus)

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, PPARα 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. Conclusion: Our data show that CAR activation modulates hepatic metabolism by lowering cholesterol and glucose levels, through effects on PPARα and adiponectin signaling pathways, and by compromising liver adaptations to hyperlipidemia.

Original languageEnglish
Article number1471
Pages (from-to)384
Number of pages1
JournalBMC Genomics
Volume10
DOIs
Publication statusPublished - Aug 19 2009

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Metabolic Networks and Pathways
Cholesterol
Liver
Hyperlipidemias
Peroxisome Proliferator-Activated Receptors
Xenobiotics
Diet
Sterol Regulatory Element Binding Protein 2
Up-Regulation
Glucose
Adipokines
Metabolome
Adiponectin
Gene Expression Profiling
Cytoplasmic and Nuclear Receptors
constitutive androstane receptor
Bile Acids and Salts
Serum
Transcriptome
Genes

ASJC Scopus subject areas

  • Biotechnology
  • Genetics

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Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers. / Režen, Tadeja; Tamási, V.; Lövgren-Sandblom, Anita; Björkhem, Ingemar; Meyer, Urs A.; Rozman, Damjana.

In: BMC Genomics, Vol. 10, 1471, 19.08.2009, p. 384.

Research output: Contribution to journalArticle

Režen, Tadeja ; Tamási, V. ; Lövgren-Sandblom, Anita ; Björkhem, Ingemar ; Meyer, Urs A. ; Rozman, Damjana. / Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers. In: BMC Genomics. 2009 ; Vol. 10. pp. 384.
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