Abstract 15483: FoxO1 Mediates an Auto-feedback Loop Regulation of SIRT1 Expression
Forkhead transcription factor FoxO1 and the NAD+-dependent histone deacetylase SIRT1 are evolutionarily conserved regulators of the development of aging, oxidative stress resistance, insulin resistance, and metabolism regulation in species ranging from invertebrates to mammals. SIRT1 deacetylates FoxO1 and enables activation of FoxO1 transcription in multiple systems. The functional consequences of the interactions between FoxO1 and SIRT1 remain incompletely understood. Here, we demonstrate that the 1.5 kb rat SIRT1 promoter region contains a cluster of five putative FoxO1 core binding repeat motifs (designated IRS-1abcde, ACAAAAA, from -973 to -732) and a forkhead-like consensus binding site (designated FKHD-L, TATGTAAATA, from -370 to -361). Luciferase promoter assays demonstrate that FoxO1 directly activates SIRT1 promoter activity and that both the IRS-1 and FKHD-L enable FoxO1-dependent SIRT1 transcription. Electrophoretic mobility shift assays and chromatin immunoprecipitation assays show that FoxO1 binds to the IRS-1 and FKHD-L sites of the SIRT1 promoter in vitro and in situ. Consistently, FoxO1 overexpression increases SIRT1 expression and FoxO1 depletion by siRNA reduces SIRT1 expression at both the messenger RNA and protein levels. Thus, endogenous FoxO1 is a positive transcriptional regulator of SIRT1 through the direct binding to the two cis-acting elements in the SIRT1 promoter. Conversely, SIRT1 promotes FoxO1-driven SIRT1 auto-transcription through interacting with and deacetylating FoxO1. Moreover, resveratrol, a plant polyphenol activator of SIRT1, increases FoxO1-dependent SIRT1 transcription activity and thus induces its expression in rat vascular smooth muscle cells. These findings suggest that positive feedback mechanisms regulate FoxO1-dependent SIRT1 transcription and imputes a previously unappreciated function for FoxO1. The activity of this signaling network may sustain a variety of salutatory influences upon immune, inflammatory, regenerative, and metabolic processes that inform understanding of mechanistically related chronic diseases such as those associated with the metabolic syndrome.
- © 2010 by American Heart Association, Inc.