Tissue- and Nuclear Receptor-Specific Function of the C-Terminal LXXLL Motif of Coactivator NCoA6/AIB3 in Mice

Although the LXXLL motif of nuclear receptor (NR) coactivators is essential for interaction with NRs, its role has not been assessed in unbiased animal models. The nuclear receptor coactivator 6 (NCoA6; also AIB3, PRIP, ASC-2, TRBP, RAP250, or NRC) is a coactivator containing an N-terminal LXXLL-1 (L1) and a C-terminal L2. L1 interacts with many NRs, while L2 interacts with the liver X receptor alpha (LXRalpha) and the estrogen receptor alpha (ERalpha). We generated mice in which L2 was mutated into AXXAL (L2m) to disrupt its interaction with LXRalpha and ERalpha. NCoA6(L2m/L2m) mice exhibited normal reproduction, mammary gland morphogenesis, and ERalpha target gene expression. In contrast, when treated with an LXRalpha agonist, lipogenesis and the LXRalpha target gene expression were significantly reduced in NCoA6(L2m/L2m) mice. The induction of Cyp7A1 expression by a high-cholesterol diet was impaired in NCoA6(L2m/L2m) mice, which reduced bile acid synthesis in the liver and excretion in the feces and resulted in cholesterol accumulation in the liver and blood. These results demonstrate that L2 plays a tissue- and NR-specific role: it is required for NCoA6 to mediate LXRalpha-regulated lipogenesis and cholesterol/bile acid homeostasis in the liver but not required for ERalpha function in the mammary gland.