Peripheral Circadian Oscillators: Time and Food - Progress in Molecular Biology and Translational Science - page 94

but not in AMPK alpha 2 knockout mice. 80 It has been demonstrated also that
AMPKphosphorylates and destabilizes the clock component cryptochrome 1.
In vivo , stimulation of AMPK destabilized cryptochromes in the liver and
altered circadian rhythms, and mice in which the AMPK pathway was genet-
ically disrupted showed alterations in peripheral clocks. 25 The following are
other sets of interactions of AMPK with the molecular clock machinery.
AMPK is a master controller of PGC-1a, a transcriptional coactivator that
orchestrates a constellation of transcription factors, such as the PPARs among
others, to induce mitochondrial gene expression. Additionally, AMPK seems
to influence SIRT1 activity through an AMPK-induced modulation of
NAD þ metabolites. Pharmacological or physiological activation of AMPK
is followed by a robust increase in NAD þ within hours, promoted by an
increase in fatty acid oxidation rates. This increase in NAD þ levels is sustained
by the induction of Nampt expression, the gene that encodes the enzyme that
resynthesizes NAD þ from its metabolic breakdown product, nicotinamide.
This constitutes a two-way impact of AMPK on SIRT1 activity as it generates
the SIRT1 activator NAD þ , while reducing the levels of nicotinamide, a
physiological inhibitor of SIRT1 activity. 81 Recent reports indicate that indi-
rectly, SIRT1 enhances AMPK activation in the liver, creating a positive-
feedback loop. 82
8. HEME AS ANOTHER METABOLIC CLOCK CONNECTION
POSSIBILITY
Heme is better known for its major role as the prosthetic group of
hemoglobin in erythrocytes; however, it has other multiple actions. Heme
consists of an iron atom surrounded by a porphyrin ring structure. The first
step in its biosynthesis is the condensation of one aminoacid (glycine) with
one intermediate of Krebs cycle (succinyl CoA) to form 5-aminolevulinate
(ALA) and CO 2 . The enzyme responsible for this rate-limiting step is the
ALA synthase (ALAS). 83 A connection with the molecular clock is suggested
by the fact that the ALAS1 is a PGC1alpha target gene. 84 A second connec-
tion is that heme is the endogenous ligand for Rev-erbalpha, the transcrip-
tion factor which is part of the accessory loop that regulates the transcription
of Bmal1 gene. 85 NPAS2, a mammalian transcription factor part of the
molecular clock system which dimerizes with BMAL1, binds heme as a
prosthetic group and at least in vitro , the heme status controls its DNA bind-
ing. 86 Interestingly, it seems that heme is connected to the clock from its
beginnings to its end. The enzyme responsible for heme degradation is