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

Abstract

The liver X receptor alpha (LXRalpha) is a member of the nuclear hormone receptor superfamily that plays an important role in lipid homeostasis. Here we characterize two alternative human LXRalpha transcripts, designated LXRalpha2 and LXRalpha3. All three LXRalpha isoforms are derived from the same gene via alternative splicing and differential promoter usage. The LXRalpha2 isoform lacks the first 45 amino acids of LXRalpha1, and is generated through the use of a novel promoter and first exon. LXRalpha3 lacks 50 amino acids within the ligand binding domain and is generated through alternative recognition of the 3'-splice site in exon 6. LXRalpha2 and LXRalpha3 are expressed at lower levels compared with LXRalpha1 in most tissues, except that LXRalpha2 expression is dominant in testis. Both LXRalpha2 and LXRalpha3 heterodimerize with the retinoid X receptor and bind to LXR response elements. LXRalpha2 shows reduced transcriptional activity relative to LXRalpha1, indicating that the N-terminal domain of LXRalpha is essential for its full transcriptional activity. LXRalpha3 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 LXRalpha transcripts in certain biological contexts may impact LXR signaling and lipid metabolism.