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 260

11.3 Substrate Supply and Its Regulation (Randle and
Krebs Cycles)

11.3.1 Mechanisms of Regulation of Fatty Acids Oxidation
in Heart Muscle

Fatty acids are released from triacylglycerol (TAG) by activated lipoprotein lipase
(LPL) and transferred in the cytoplasm bound to proteins. Free fatty acid transfer
across mitochondrial membranes consumes ATP involving FFA conversion into an
Acyl-CoA derivative and the transport-competent acyl-carnitine form by carnitine
palmitoyl transferase (CPT). The MOM-localized CPT1 targeted by malonyl CoA
inhibition constitutes an important regulatory step of β -oxidation of FAs ( β -FAO)

(Fig. 11.4 ) (Saks et al. 2006b ). -FAO is linked to the citric acid cycle and oxidative

phosphorylation through NAD + , FAD, and acyl-CoA. The NADH generated by the
Krebs cycle and

β

-FAO is oxidized in the electron transport chain. Increased ATP
utilization elicits ATP synthesis driven by the proton motive force, thus decreasing
the NADH/NAD + ratio. Oxidation of the NADH pool increases the flux through the
Krebs

β

through NAD + -dependent

-ketoglutarate
deshydrogenases, thus decreasing acetyl-CoA (AcCoA) levels. NAD + can also be
reduced in

cycle isocitrate and α

-hydroxyacyl-CoA dehydrogenase and in the
glycolytic pathway catalyzed by glyceraldehyde phosphate dehydrogenase
(GAPDH). However, the transfer of NADH reduction potential from glycolysis
towards the mitochondrial matrix via the malate-aspartate shuttle, being slower
than direct NAD+ use by

β -FAO catalyzed by β

-FAO, will prioritize the latter one (Kobayashi and Neely
1979 ). Thus, the GAPDH dependence on cytoplasmic NADH/NAD + ratio
associated with the slow kinetics of malate-aspartate shuttle will rather slow
down glycolysis. An increase in the rate of AcCoA utilization by the Krebs cycle
will thus increase

β

β -FAO. An accumulation of AcCoA does not influence signifi-

cantly the rate of -FAO due to the equilibrium constant of the reversible thiolase

reaction which is in favor of AcCoA production (Neely and Morgan 1974 ).
At low ATP demand (decreased workload), the high NADH/NAD + ratio slows
down the flux through NAD + -dependent dehydrogenases, thus decreasing the rate
of AcCoA oxidation through the Krebs cycle. An increased intra-mitochondrial
AcCoA level is thought to favor its transfer towards the cytoplasm where it is
converted into malonyl-CoA, an inhibitor of CPT-1-controlled FA transport into
mitochondria. Malonyl-CoA levels are also controlled by acetyl-coA carboxylase
(ACC), a cytosolic enzyme catalyzing conversion of AcCoA into malonyl-CoA,
whose inactivation by AMPK during energy stress relieves CPT1 inhibition.
Preferential utilization of FAs involves inhibition of glucose transport, phospho-
fructokinase (PFK), and pyruvate dehydrogenase (PDH) reactions (Hue and
Taegtmeyer 2009 ; Taegtmeyer 2010 ; Taegtmeyer et al. 2005 ). Glucose transport
in muscle cells is realized through GLUT4, the expression of which in the sarco-
lemma is regulated by insulin and other signals. Increased NADH/NAD+ and

β