Among the members of the additional sex comb-like (ASXL) family, ASXL3 remains unexplored. Here, we showed that ASXL3 interacts with HP1 alpha and LSD1, leading to transcriptional repression. We determined that ASXL3 depletion augments the ligand-induced transcriptional activities of LXR alpha and TR beta, which were repressed by ASXL3 overexpression. The ligand-dependent interactions of ASXL3 with LXR alpha and TR beta were demonstrated by the GST pull-down and immunoprecipitation analyses. We confirmed that ASXL3 suppresses the expression of LXR alpha target genes through its recruitment to the LXR-response elements. Finally, we observed that lipid accumulation in Hep3B cells is downregulated upon ASXL3 overexpression but upregulated upon ASXL3 depletion. Overall, our data suggest that ASXL3 is another corepressor of LXRa, promoting to the regulation of lipid homeostasis. (C) 2014 Elsevier Inc. All rights reserved.