The
NAD(+)-dependent deacetylase
SIRT1 is a key regulator of several aspects of metabolism and aging.
SIRT1 activation is beneficial for several human diseases, including
metabolic syndrome, diabetes,
obesity,
liver steatosis, and
Alzheimer disease. We have recently shown that the
protein deleted in
breast cancer 1 (DBC1) is a key regulator of
SIRT1 activity in vivo. Furthermore,
SIRT1 and DBC1 form a dynamic complex that is regulated by the energetic state of the organism. Understanding how the interaction between
SIRT1 and DBC1 is regulated is therefore essential to design strategies aimed to activate
SIRT1. Here, we investigated which pathways can lead to the dissociation of
SIRT1 and DBC1 and consequently to
SIRT1 activation. We observed that PKA activation leads to a fast and transient activation of
SIRT1 that is DBC1-dependent. In fact, an increase in cAMP/PKA activity resulted in the dissociation of
SIRT1 and DBC1 in an
AMP-activated protein kinase (AMPK)-dependent manner. Pharmacological AMPK activation led to
SIRT1 activation by a DBC1-dependent mechanism. Indeed, we found that AMPK activators promote SIRT1-DBC1 dissociation in cells, resulting in an increase in
SIRT1 activity. In addition, we observed that the
SIRT1 activation promoted by PKA and AMPK occurs without changes in the intracellular levels of
NAD(+). We propose that PKA and AMPK can acutely activate
SIRT1 by inducing dissociation of
SIRT1 from its endogenous inhibitor DBC1. Our experiments provide new insight on the in vivo mechanism of
SIRT1 regulation and a new avenue for the development of pharmacological
SIRT1 activators targeted at the dissociation of the SIRT1-DBC1 complex.