TY - JOUR T1 - Differential Expression and Function of Alternative Splicing Variants of Human Liver X Receptor α JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.111.077206 SP - mol.111.077206 AU - Kaori Endo-Umeda AU - Shigeyuki Uno AU - Ko Fujimori AU - Yoshikazu Naito AU - Koichi Saito AU - Kenji Yamagishi AU - Yangsik Jeong AU - Hiroyuki Miyachi AU - Hiroaki Tokiwa AU - Sachiko Yamada AU - Makoto Makishima Y1 - 2012/01/01 UR - http://molpharm.aspetjournals.org/content/early/2012/03/07/mol.111.077206.abstract N2 - The liver X receptor α (LXRα) 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 LXRα isoforms with variation in the ligand-binding domain (LBD). While examining the expression of LXRα3, which lacks 60 amino acids within the LBD, we identified two novel transcripts, which encode LXRαLBD variants (LXR[alpha]4 and LXRα5). LXRα4 has an insertion of 64 amino acids in helix 4/5, and LXRα5 lacks the C-terminal helices 7-12 due to a termination codon in an additional exon that encodes an intron in the LXRα1 mRNA. LXRα3, LXRα4 and LXRα5 were expressed at lower levels when compared with LXRα1 in many human tissues and cell lines. We also observed weak expression of LXRα3 and LXRα4 in several tissues of mice. LXR ligand treatment induced differential regulation of LXRα isoform mRNA expression in a cell type-dependent manner. While LXRα3 had no effect, LXRα4 has weak transactivation, RXR heterodimerization, and coactivator recruitment activities. LXRα5 interacted with a corepressor in a ligand-independent manner and inhibited LXRα1 transactivation and target gene expression when overexpressed. Combination of LXRα5 cotransfection and LXRα antagonist treatment produced additive effects on the inhibition of ligand-dependent LXRα1 activation. We constructed structural models of the LXRα4-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 LXRα pre-mRNA splicing may be involved in the pathogenesis of LXRα-related diseases. ER -