Differential Expression and Function of Alternative Splicing Variants of Human Liver X Receptor α

The liver X receptor alpha (LXR alpha) is a nuclear receptor that is involved in regulation of lipid metabolism, cellular proliferation and apoptosis, and immunity. In this report, we characterize three human LXR alpha isoforms with variation in the ligand-binding domain (LBD). While examining the expression of LXR alpha 3, which lacks 60 amino acids within the LBD, we identified two novel transcripts that encode LXR alpha-LBD variants (LXR alpha 4 and LXR alpha 5). LXR alpha 4 has an insertion of 64 amino acids in helix 4/5, and LXR alpha 5 lacks the C-terminal helices 7 to 12 due to a termination codon in an additional exon that encodes an intron in the LXR alpha 1 mRNA. LXR alpha 3, LXR alpha 4, and LXR alpha 5 were expressed at lower levels compared with LXR alpha 1 in many human tissues and cell lines. We also observed weak expression of LXR alpha 3 and LXR alpha 4 in several tissues of mice. LXR ligand treatment induced differential regulation of LXR alpha isoform mRNA expression in a cell type-dependent manner. Whereas LXR alpha 3 had no effect, LXR alpha 4 has weak transactivation, retinoid X receptor (RXR) heterodimerization, and coactivator recruitment activities. LXR alpha 5 interacted with a corepressor in a ligand-independent manner and inhibited LXR alpha 1 transactivation and target gene expression when overexpressed. Combination of LXR alpha 5 cotransfection and LXR alpha antagonist treatment produced additive effects on the inhibition of ligand-dependent LXR alpha 1 activation. We constructed structural models of the LXR alpha 4-LBD and its complexes with ligand, RXR-LBD, and coactivator peptide. The models showed that the insertion in the LBD can be predicted to disrupt RXR heterodimerization. Regulation of LXR alpha pre-mRNA splicing may be involved in the pathogenesis of LXR alpha-related diseases.