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Israël. J Cancer Metastasis Treat 2019;5:12 I http://dx.doi.org/10.20517/2394-4722.2018.78 Page 9 of 12

transamination chain as indicated, forming pyruvate that feeds, via Pcarb and PEPCK the neoglucogenic
pathway. There is also an activation of the urea cycle. In parallel to neoglucogenesis, glucose is also produced
by glycogenolysis (phosphorylase a, is ON). The transaminations are interacting as indicated in Figure 2,
with the mitochondria shuttle. Note that PKA-Src activates LKB1, which stimulates AMP kinase, this
closes the fatty acid synthesis pathway (AMP kinase inhibits ACC). Now fatty acids provided by adipocyte
lipolysis, get transported in the liver cell mitochondria since malonyl CoA is low, their beta oxidation forms
acetyl CoA. With the NADH being elevated, the citrate condensation is inhibited. Thus, acetyl CoA in excess
will follow the ketogenic route giving acetoacetate. Note that growth hormone stimulates ATGL and DAG
formation, which stimulates PKC and the CPI17 inhibitor of phosphatase PP1, maintaining the inhibition
of PK and PDH, which closes the glycolytic entry of the citric acid cycle. The stimulation of PKC should
activate AMP deaminase, decreasing AMP and the stimulation of AMP kinase, but AMP kinase is already
efficiently activated by LKB1, which maintains the inhibition of the fatty acid synthesis pathway. Note also
that the ATP/AMP ratio that controls the citrate efflux via the inhibition of isocitrate dehydrogenase by ATP
is not operational here, since the above reaction, the citrate condensation, is already inhibited by an elevated
NADH/NAD ratio. Presumably a low supply of glucose decreases 2-3DPG in erythrocytes, less oxygen is
delivered and reduced by the liver cell and fewer electrons are pulled away from NADH, which inhibits the
citrate condensation reaction. Probably, less lactic acid is released by liver cells, since pyruvate feeds the
neoglucogenic route, rather than lactate dehydrogenase, which locally decreases the Bohr Effect and oxygen
supply to the liver. This liver cell is programmed to feed the above stem cell with nutrients, glucose and
particularly ketone bodies, while receiving amino acids from muscle, and fatty acids from adipose tissue.

The bottom cell in Figure 2 is a muscle cell; again, it is resistant to insulin like other differentiated cells, and
receives the catabolic part of the hybrid pancreatic message. For muscles, epinephrine rather than glucagon,
activates via Gs coupled beta adrenergic receptors, adenylate cyclase and PKA-Src. But here, there is a
muscle specificity that has to maintain glycolysis as discussed earlier. Muscle activity releases calcium from
internal stores, stimulating a PDE that hydrolyses cAMP, this cancels the inhibition by cAMP on Fruc2-6 bis
P formation; the increase of this allosteric activator of glycolysis at the phospho fructokinase 1 step, boosts
glycolysis, while calcium stimulates the membrane incorporation of the glucose transporter. In addition, the
alpha epinephrine receptors of Go or Gi type are predominant in muscle limiting the increase cAMP, via Gs
coupled beta adrenergic receptors. Calcium should also activate calcineurin phosphatase and neutralize the
inhibition of PP1 by I1 in order to open back PK and PDH by de-phosphorylation, but here the activation of
PKC by DAG forms the CPI 17 inhibitor of PP1 closing the glycolytic acetyl CoA supply. This DAG is formed
by ATGL stimulated by GH; we explained above that the GABA deficit elicits the release of epinephrine
that blocks efficiently delta cells, decreasing STH, which stimulates GH and ATGL. As occurred for the
liver cell, the LKB1 stimulation of AMP kinase inhibits ACC and closes the fatty acid synthesis route, which
automatically opens the beta oxidation of fatty acids into acetyl CoA. But in contrast to the liver cell, the
citrate condensation is operational in muscle. It is activated by the decrease of NADH resulting from the
increased reduction of oxygen. Indeed, the lactic acid released supports the Bohr Effect, which liberates more
oxygen from oxy- hemoglobin in acid conditions. Moreover, muscle myoglobin pulls more oxygen into the
muscle. The condensation of acetyl CoA coming from fatty acids, and OAA provided by PEP, above the PK
bottle neck, forms citrate. The efflux of citrate will not feed the fatty acid synthesis, we have seen that the
pathway was closed (via the activation of AMP kinase by LKB1) thus citrate will be processed by the Krebs
cycle. Muscle activity consumes ATP and forms AMP; since ATP is lowered, it does not inhibit isocitrate
dehydrogenase, the citric acid cycle “turns”. Another essential point is that cortisol stimulates proteolysis in
muscle; indeed, glucagon increases ACTH release and the release of cortisol from adrenals. Note that the
amino acids will feed the liver cell forming glucose, and the stem cell synthesizing its proteins; follow the
interaction of the amino acids with the transaminases and mitochondrial shuttle, and the lactic acid release
for both stem cells and muscle supporting locally a Bohr Effect. In liver cells, pyruvate will preferentially
follow the neoglucogenic route, and less goes to lactate dehydrogenase.