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

Mingyi Chen, Simon W. Beaven, and Peter Tontonoz

Howard Hughes Medical Institute, UCLA School of Medicine, Los Angeles, CA 90095-1662

Corresponding Author: ptontonoz{at}mednet.ucla.edu

The liver X receptor alpha (LXR $alpha$ ) is a member of the nuclear hormone receptor superfamily that plays an important role in lipid homeostasis. Recent studies have demonstrated the importance of LXR signaling pathways in the development of metabolic disorders such as hyperlipidemia and atherosclerosis. Here we characterize two alternative human LXR $alpha$ transcripts, designated LXR $alpha$ 2 and LXR $alpha$ 3. All three human LXR $alpha$ isoforms are derived from the same gene via alternative splicing and differential promoter usage. The LXR $alpha$ 2 isoform lacks the first 45 amino acids of LXRa1. It is generated by through use of a novel promoter and first exon (designated 1c), which is nearly 10 kb upstream of the original exon 1a. LXR $alpha$ 3 lacks 50 amino acids within the ligand-binding domain and is generated through alternative recognition of the 3'-splice site in exon 6. LXR $alpha$ 2 and LXR $alpha$ 3 are expressed at lower levels compared with LXR $alpha$ 1 in most tissues, except that LXR $alpha$ 2 expression is dominant in testis. Both LXR $alpha$ 2 and LXR $alpha$ 3 heterodimerize with RXR and bind to LXR response elements. LXR $alpha$ 2 shows reduced transcriptional activity relative to LXR $alpha$ 1, indicating that the N-terminal domain of LXR $alpha$ is essential for its full transcriptional activity. LXR $alpha$ 3 is unable to bind ligand and is transcriptionally inactive, but does not function as a dominant negative receptor. These observations outline a previously unrecognized role for the N-terminus in LXR function and suggest that the expression of alternative LXR $alpha$ transcripts in various cell types or biological contexts may impact LXR signaling and lipid metabolism.

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