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. 2009 Aug 19:10:384.
doi: 10.1186/1471-2164-10-384.

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

Tadeja Rezen  1 , Viola Tamasi, Anita Lövgren-Sandblom, Ingemar Björkhem, Urs A Meyer, Damjana Rozman
Affiliations

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

Tadeja Rezen et al. BMC Genomics. .

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.

Conclusion: 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.

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Figures

Figure 1
Figure 1
Liver sterol profiles in TCPOBOP treated mice. Liver sterol profiles in mice as measured by GC-MS (3 biological samples per group) fed either standard (light box) or 1% cholesterol diet (dark box), and treated either vehicle or TCPOBOP. p-values are indicated between different groups. A. Total liver cholesterol level (ng/mg liver). B. Free lathosterol/total cholesterol level ratio indicates the metabolic rate of liver cholesterol biosynthesis. C. Free C4 (7-α-hydroxy-4-cholestene-3-one)/total cholesterol ratio. C4 is an intermediate in bile acid biosynthesis and shows a metabolic rate of the classical CYP7A1 pathway.
Figure 2
Figure 2
Effects of TCPOBOP and cholesterol diet on liver cholesterol homeostasis. Effects of TCPOBOP and cholesterol diet on liver cholesterol metabolism. A. Effects of TCPOBOP in conditions of normal diet. B. Effects of 1 week 1% cholesterol diet. C. Effects of TCPOBOP in conditions of high-cholesterol diet. Bold solid arrow – increase, solid arrow – no change, dashed arrow – decrease.
Figure 3
Figure 3
Effects of TCPOBOP and cholesterol diet on liver glucose and triglyceride metabolism. Proposed effects of TCPOBOP and cholesterol diet on liver glucose and triglyceride metabolism. A. Effects of TCPOBOP in conditions of normal diet. B. Effects of 1 week 1% cholesterol diet. C. Effects of TCPOBOP in conditions of high-cholesterol diet. Bold solid arrow – increase, solid arrow – no change, dashed arrow – decrease.
Figure 4
Figure 4
Representative immunoblot analysis of nuclear SREBP2 in mouse liver. Representative immunoblot analysis of nuclear SREBP2 in the liver of mice on standard or cholesterol diet and treated with TCPOBOP. No activation of SREBP2 was observed after TCPOBOP application. Diet: ST – standard diet, CH – cholesterol diet.
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