Constitutive androstane receptor activation decreases plasma apolipoprotein B-containing lipoproteins and atherosclerosis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2011 Oct;31(10):2232-9
Date
07/23/2011Pubmed ID
21778422Pubmed Central ID
PMC4104927DOI
10.1161/ATVBAHA.110.222497Scopus ID
2-s2.0-80052964598 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
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.
Author List
Sberna AL, Assem M, Xiao R, Ayers S, Gautier T, Guiu B, Deckert V, Chevriaux A, Grober J, Le Guern N, Pais de Barros JP, Moore DD, Lagrost L, Masson DAuthor
Mahfoud Assem PharmD Associate Professor in the School of Pharmacy Administration department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Apolipoprotein B-100
Apolipoproteins B
Apolipoproteins E
Atherosclerosis
Cholesterol
Cholesterol, LDL
Disease Models, Animal
Down-Regulation
Female
Genes, Reporter
HEK293 Cells
Hep G2 Cells
Humans
Hyperlipidemias
Lipogenesis
Lipoproteins
Lipoproteins, VLDL
Liver
Mice
Mice, Inbred C57BL
Mice, Knockout
Molecular Sequence Data
Pyridines
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Receptors, LDL
Response Elements
Time Factors
Transfection
Triglycerides