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 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.
Wang
Yongjun
Y
Nuclear Receptor Biology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana 70808, USA.
Rogers
Pamela M
PM
Su
Chen
C
Varga
Gabor
G
Stayrook
Keith R
KR
Burris
Thomas P
TP
D050197:Atherosclerosis / Q000378:metabolism; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000096:biosynthesis*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000096:biosynthesis*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D006801:Humans; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology*; D058886:Sterol 14-Demethylase; D014158:Transcription, Genetic / Q000502:physiology*
C548418:CYP51A1 protein, human; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D058886:Sterol 14-Demethylase; D013186:Farnesyl-Diphosphate Farnesyltransferase