FIGURE 9.

A proposed molecular mechanism by which p300 coactivates ligand-activated FXR induction of SHP. Unliganded FXR/RXR heterodimer is associated with the SHP promoter and acetylated histone H3 levels are minimal, resulting in basal levels of SHP expression. Activation of FXR signaling by bile acids or GW4064 increases the FXR interaction with p300 and recruits p300 to the SHP promoter. The recruited p300 increases both histone H3 acetylation at K9/14 (a gene activation histone mark) and FXR acetylation, which would increase the association of FXR, coactivator complexes, and RNA polymerase II with the SHP promoter (the solid circle denotes increased FXR binding, compared with the dotted circle in the basal state). These processes at the promoter lead to the SHP gene induction in hepatocytes in response to ligand-activated FXR signaling.