Systems Level Regulation of Cardiac Energy Fluxes Via Metabolic Cycles: Role of Creatine, Phosphotransfer Pathways, and AMPK Signaling - Systems Biology of Metabolic and Signaling Networks - page 290

autophagy, and central functions like appetite control. To date, about 50 AMPK
substrates have been described in different tissues, including metabolic enzymes,
transcription (co)factors, and other cellular signaling elements. They all are
activated or inactivated by phosphorylation at Thr or Ser residues within a more
or less conserved AMPK recognition motif. We will give here only some examples
pertinent to heart; more complete descriptions can be found in recent reviews
(Hardie et al. 2012a , b ; Carling et al. 2012 ; Steinberg and Kemp 2009 ).

11.5.5.1 Metabolic Pathways

AMPK control of cellular substrate uptake, transport, and metabolism is the histor-
ically best described and possibly most important function of AMPK, also in the
heart, since it is critical for ATP generation (Fig. 11.5 ). Activated AMPK stimulates
cellular glucose and fatty acid uptake via translocation of GLUT4 (Kurth-Kraczek
et al. 1999 ; Yamaguchi et al. 2005 ) and FAT/CD36 (van Oort et al. 2009 ), respec-
tively, to the plasma membrane, involving among others phosphorylation of the
Rab-GTPase activating protein TBC1D1 (Frosig et al. 2010 ). The subsequent
substrate flux via glycolysis is increased by phosphorylation and activation of
6-phosphofructosekinase-2 (PFK2), whose product fructose-2,6-bisphosphate is
an allosteric activator of the glycolytic enzyme 6-phosphofructokinase-1 (Marsin
et al. 2000 ) and in long term by stimulation of hexokinase II (HKII) transcription
(Stoppani et al. 2002 ). Substrate flux via fatty acid -oxidation is increased by

inhibition of mitochondria-associated acetyl-CoA carboxylase (ACC2), whose
product malonyl-CoA is an allosteric inhibitor of carnitine palmitoyltransferase
1 (CPT1), the rate-limiting enzyme for of mitochondrial fatty acid import and
oxidation (Merrill et al. 1997 ). At the same time, inhibition of cytosolic ACC1
will repress ATP-consuming fatty acid synthesis for which malonyl-CoA is the
precursor (Davies et al. 1992 ). In other organs with multiple anabolic functions like
liver, several other anabolic pathways like gluconeogenesis or triglyceride and
cholesterol synthesis are inhibited (Bultot et al. 2012 ; Muoio et al. 1999 ; Clarke
and Hardie 1990 ).
Active AMPK also affects gene expression of many of these metabolic enzymes
by phosphorylation of transcription (co)factors and histone deacetylases (HDACs).
Activation of peroxisome proliferator-activated receptor gamma co-activator-1
alpha (PGC-1

β

) increases the expression of nuclear-encoded mitochondrial genes
that favor mitochondrial biogenesis (Irrcher et al. 2003 ; Jager et al. 2007 ), and
further catabolic genes including substrate transporters (e.g., GLUT4). Mainly in
the liver, expression of several genes in anabolic lipogenesis (e.g., ACC1) and
gluconeogenesis is reduced via inhibition of ChREBP or SREBP (Kawaguchi
et al. 2002 ; Li et al. 2011 ) and CRTC2 or class II HDACs (Koo et al. 2005 ;
Mihaylova et al. 2011 ), respectively. Cellular redox regulation by AMPK also
occurs mainly at the transcriptional level. AMPK directly phosphorylates transcrip-
tion factor FOXO3, which increases transcription of many genes, mainly in oxida-
tive stress defense (Greer et al. 2007 ) and activates, possibly more indirectly, class

α