Ultimately, the apparent differences in severity of the damaging phenotype observed in SIRT1‐overexpressing mice when compared to SIRT1hep–/– mice, despite the similarly attenuation of FXR signaling, support that apoptotic cell death associated with increased SIRT1 expression play a key role in contributing to liver injury during cholestasis. This evidence concerns the gene NR1H4 and cholestasis.