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

The liver X receptor α (LXRα) is a member of the nuclear hormone receptor superfamily that plays an important role in lipid homeostasis. Here we characterize two alternative human LXRα transcripts, designated LXRα2 and LXRα3. All three LXRα isoforms are derived from the same gene via alternative splicing and differential promoter usage. The LXRα2 isoform lacks the first 45 amino acids of LXRα1, and is generated through the use of a novel promoter and first exon. LXRα3 lacks 50 amino acids within the ligand binding domain and is generated through alternative recognition of the 3′-splice site in exon 6. LXRα2 and LXRα3 are expressed at lower levels compared with LXRα1 in most tissues, except that LXRα2 expression is dominant in testis. Both LXRα2 and LXRα3 heterodimerize with the retinoid X receptor and bind to LXR response elements. LXRα2 shows reduced transcriptional activity relative to LXRα1, indicating that the N-terminal domain of LXRα is essential for its full transcriptional activity. LXRα3 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 LXRα transcripts in certain biological contexts may impact LXR signaling and lipid metabolism.