Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice.

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.

METHODS AND 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.