Induction of human liver X receptor alpha gene expression via an autoregulatory loop mechanism.
The liver X receptors (LXRs), members of the nuclear receptor superfamily, play an important role in controlling lipid homeostasis by activating several genes involved in reverse cholesterol transport. These include members of the ATP binding cassette (ABC) superfamily of transporter proteins ABCA1 and ABCG1, surface constituents of plasma lipoproteins like apolipoprotein E, and cholesterol ester transport protein. They also play an important role in fatty acid metabolism by activating the sterol regulatory element-binding protein 1c gene. Here, we identify human LXRalpha (hLXRalpha) as an autoinducible gene. Induction in response to LXR ligands is observed in multiple human cell types including macrophages and occurs within 2--4 h. Analysis of the hLXRalpha promoter revealed three LXR response elements (LXREs); one exhibits strong affinity for both LXRalpha:RXR and LXRbeta:RXR (a type I LXRE), and deletion and mutational studies indicate it plays a critical role in LXR-mediated induction. The other two LXREs are identical to each other, exist within highly conserved Alu repeats, and exhibit selective binding to LXRalpha:RXR (type II LXREs). In transfections, the type I LXRE acts as a strong mediator of both LXRalpha and LXRbeta activity, whereas the type II LXRE acts as a weaker and selective mediator of LXRalpha activity. Our data suggest a model in which LXR ligands trigger an autoregulatory loop leading to selective induction of hLXRalpha gene expression. This would lead to increased hLXRalpha levels and transcription of its downstream target genes such as ABCA1, providing a simple yet exquisite mechanism for cells to respond to LXR ligands and cholesterol loading.
Li
Yu
Y
Department of Biotechnology, Mail Zone AA305E, Pharmacia Corp., St. Louis, Missouri 63198, USA.
Bolten
Charles
C
Bhat
B Ganesh
BG
Woodring-Dietz
Jessica
J
Li
Suzhen
S
Prayaga
Sudhirdas K
SK
Xia
Chunsheng
C
Lala
Deepak S
DS
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001483:Base Sequence; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D017737:Macrophages, Peritoneal / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016297:Mutagenesis, Site-Directed; D057093:Orphan Nuclear Receptors; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D020218:Response Elements; D012867:Skin; D013449:Sulfonamides; D014162:Transfection; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008024:Ligands; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D013449:Sulfonamides; C577836:ABCA1 protein, human; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides