Regulation of cholesterologenesis by the oxysterol receptor, LXRalpha

Cholesterol is required for normal cellular and physiological function, yet dysregulation of cholesterol metabolism is associated with diseases such as atherosclerosis. Cholesterol biosynthesis is regulated by end product negative feedback inhibition where the levels of sterols and oxysterols regula...

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Bibliographic Details
Published in:The Journal of biological chemistry 2008-09, Vol.283 (39), p.26332-26339
Main Authors: Wang, Yongjun, Rogers, Pamela M, Su, Chen, Varga, Gabor, Stayrook, Keith R, Burris, Thomas P
Format: Article
Language:English
Subjects:
Atherosclerosis - metabolism
Cell Line, Tumor
Cholesterol - biosynthesis
Cytochrome P-450 Enzyme System - biosynthesis
DNA-Binding Proteins - metabolism
Farnesyl-Diphosphate Farnesyltransferase - biosynthesis
Gene Expression Regulation, Enzymologic - physiology
Gene Silencing - physiology
Humans
Liver X Receptors
Orphan Nuclear Receptors
Receptors, Cytoplasmic and Nuclear - metabolism
Response Elements - physiology
Sterol 14-Demethylase
Transcription, Genetic - physiology
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Summary:Cholesterol is required for normal cellular and physiological function, yet dysregulation of cholesterol metabolism is associated with diseases such as atherosclerosis. Cholesterol biosynthesis is regulated by end product negative feedback inhibition where the levels of sterols and oxysterols regulate the expression of cholesterologenic enzymes. Sterol regulatory element-binding protein-2 is responsive to both sterols and oxysterols and has been shown to mediate the transcriptional response of the cholesterologenic enzymes to these lipids. Here, we show that the nuclear hormone receptor for oxysterols, the liver X receptor alpha (LXRalpha), regulates cholesterol biosynthesis by directly silencing the expression of two key cholesterologenic enzymes (lanosterol 14alpha-demethylase (CYP51A1), and squalene synthase (farnesyl diphosphate farnesyl transferase 1)) via novel negative LXR DNA response elements (nLXREs) located in each of these genes. Examination of the CYP51A1 gene revealed that both the SRE and nLXRE are required for normal oxysterol-dependent repression of this gene. Thus, these data suggest that LXRalpha plays an important role in the regulation of cholesterol biosynthesis.
ISSN:0021-9258
DOI:10.1074/jbc.M804808200