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Journal of Lipid Research, Vol. 46, 2570-2579, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Identification and characterization of two alternatively spliced transcript variants of human liver X receptor alpha

Mingyi Chen^*, Simon Beaven and Peter Tontonoz^1,*,

^* Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095
Division of Digestive Diseases, Department of Medicine, University of California, Los Angeles, CA 90095
Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095

Published, JLR Papers in Press, September 16, 2005. DOI 10.1194/jlr.M500157-JLR200

¹ To whom correspondence should be addressed. e-mail: ptontonoz{at}mednet.ucla.edu

The liver X receptor (LXR) is a member of the nuclear hormone receptor superfamily that plays an important role in lipid homeostasis. Here we characterize two alternative human LXR transcripts, designated LXR2 and LXR3. All three LXR isoforms are derived from the same gene via alternative splicing and differential promoter usage. The LXR2 isoform lacks the first 45 amino acids of LXR1, and is generated through the use of a novel promoter and first exon. LXR3 lacks 50 amino acids within the ligand binding domain and is generated through alternative recognition of the 3'-splice site in exon 6. LXR2 and LXR3 are expressed at lower levels compared with LXR1 in most tissues, except that LXR2 expression is dominant in testis. Both LXR2 and LXR3 heterodimerize with the retinoid X receptor and bind to LXR response elements. LXR2 shows reduced transcriptional activity relative to LXR1, indicating that the N-terminal domain of LXR is essential for its full transcriptional activity. LXR3 is unable to bind ligand and is transcriptionally inactive.

These observations outline a previously unrecognized role for the N terminus in LXR function and suggest that the expression of alternative LXR transcripts in certain biological contexts may impact LXR signaling and lipid metabolism.

Abbreviations: AF, activation function; DBD, DNA binding domain; LBD, ligand binding domain; LXR, liver X receptor; LXRE, LXR response element; RXR, retinoid X receptor

Supplementary key words nuclear receptor • cholesterol metabolism • transcriptional regulation • RXR

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