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

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.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.The liver is the central organ of metabolic and energy homeostasis. It regulates levels of endogenous metabolites such as glucose, triglycerides and cholesterol, and detoxifies xenobiotics. These endobiotic and xenobiotic metabolic processes are frequently regulated by the same nuclear receptors. CAR, the constitutive androstane receptor, was initially described as a pure xenosensor of the liver. It activates the detoxification system in the presence of drugs and endogenous molecules, such as bile acids and bilirubin. Therefore, CAR activators are used to treat cholestasis and jaundice in humans and mice [1-4]. TCPOBOP (1,4-Bis [2-(3,5-dichloropyridyloxy)]benzene) and phenobarbital, two representative CAR activators, have strong tumor-promoting effects in mice. They increase hepatocyte prol