A 15-ketosterol is a liver X receptor ligand that suppresses sterol-responsive element binding protein-2 activity.
Hypercholesterolemia is a major risk factor for coronary artery disease. Oxysterols are known to inhibit cholesterol biosynthesis and have been explored as potential antihypercholesterolemic agents. The ability of 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one (15-ketosterol) to lower non-HDL cholesterol has been demonstrated in rodent and primate models, but the mechanisms of action remain poorly understood. Here we show in a coactivator recruitment assay and cotransfection assays that the 15-ketosterol is a partial agonist for liver X receptor-alpha and -beta (LXRalpha and LXRbeta). The binding affinity for the LXRs was comparable to those of native oxysterols. In a macrophage cell line of human origin, the 15-ketosterol elevated ATP binding cassette transporter ABCA1 mRNA in a concentration-dependent fashion with a potency similar to those of other oxysterols. We further found that in human embryonic kidney HEK 293 cells, the 15-ketosterol suppressed sterol-responsive element binding protein processing activity and thus inhibited mRNA expression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, LDL receptor, and PCSK9. Our data thus provide a molecular basis for the hypocholesterolemic activity of the 15-ketosterol and further suggest its potential antiatherosclerotic benefit as an LXR agonist.
Schmidt
Robert J
RJ
Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, IN 46285, USA.
Ficorilli
James V
JV
Zhang
Youyan
Y
Bramlett
Kelli S
KS
Beyer
Thomas P
TP
Borchert
Kristen
K
Dowless
Michele S
MS
Houck
Keith A
KA
Burris
Thomas P
TP
Eacho
Patrick I
PI
Liang
Guosheng
G
Guo
Li-Wei
LW
Wilson
William K
WK
Michael
Laura F
LF
Cao
Guoqing
G
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D002478:Cells, Cultured; D002783:Cholestenones / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000096:biosynthesis; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors*
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002783:Cholestenones; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D051782:Sterol Regulatory Element Binding Protein 2; C015073:cholest-8(14)-en-3-ol-15-one; D006903:Hydroxymethylglutaryl CoA Reductases; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases