SIRT1 regulates individual steroid hormone receptors via different mechanisms. A) SIRT1 regulates the AR through direct deacetylation, thereby inhibiting AR activation and translocation and the transcription of AR-dependent genes. B) SIRT1 inhibits the PR by regulating the nucleo-cytoplasmic translocation of the receptor, and thereby the downstream activation of PR-regulated genes. C) SIRT1 regulates ERα by inhibiting the PI3K/AKT (p85/p110) pathway, possibly through FOXO3a. This inhibits the translocation of ERα from the cytoplasm to the nucleus, thus decreasing ERα binding to DNA and ERα-dependent gene transcription. D) The energy-sensing capabilities of SIRT1 regulate its effect on GR signaling. The cellular NAD/NADH ratio regulates SIRT1-mediated deacetylation of the GR and thus its ability to interact with the co-activator p300. E) SIRT1 regulates the MR by binding DOT1, thereby enhancing DOT1-mediated repression of MR-regulated genes. SIRT1 regulation of MR is independent of SIRT1 deacetylase activity.