Figure 2.The core mechanism of the mammalian circadian clock and its link to energy metabolism.
(A) High NAD(P)H levels promote
CLOCK:BMAL1 binding to E-box sequences leading to the acetylation of BMAL1
and expression of Pers, Crys, and other clock-controlled genes. The
negative feedback loop, PERs:CRYs, binds to CLOCK:BMAL1 and consequently
PERs are acetylated. Activated AMPK leads to a rise in NAD+ levels,
phosphorylation of CRYs, and phosphorylation of CKI?, which then phosphorylates
the PERs. As a result of increased NAD+ levels, SIRT1 deacetylates PERs and BMAL1.
This and the destabilization of phosphorylated PERs and CRYs relieves PERs:CRYs
repression and another cycle starts. (B) Expression of Bmal1 and Rev-erbα
genes are controlled by PPARα and binding of RORs to RORE sequences. RORs
need a co-activator, PGC-1α, which is phosphorylated by activated AMPK. In
parallel, AMPK activation leads to an increase in NAD+ levels, which, in turn
activate SIRT1. SIRT1 activation leads to PGC-1α deacetylation and activation.
Acetyl adenosine diphosphate ribose (Ac-ADP-r) and nicotinamide (NAM) are released
after deacetylation by SIRT1.
