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Regarding the lipid metabolism, PST causes a threefold rise of free fatty acids
and glycerol release, although this effect is reversed by insulin co-stimulation
(Sanchez-Margalet and Gonzalez-Yanes 1998 ). These results are consistent with the
Chromogranin A knock-out mice model where it has been found a diminished
expression of PPAR-ɣ and Srebp 1c, two of the most important lipogenic genes.
However no changes were seen in hepatic lipids levels, probably due to an enhance-
ment of fatty acid oxidation, since there is an increase in ketone bodies levels, UCP2
expression and enhanced acetil CoA carboxylase phosphorylation (Gayen et al.
2009 ; Valicherla et al. 2013 ). In conclusion, PST seems to stimulate lipolysis rather
than lipogenesis (Carmen and Victor 2006 ).
PST has been found to act as a stimulator of protein synthesis, as well as does
insulin. Thus, insulin can induce an increment of 40% in basal protein synthesis,
and PST stimulation is able to produce a 30% increase. The mechanism used by
PST to regulate these effects seems to be the activation of ERK1/2 signaling path-
way (Sanchez-Margalet and Gonzalez-Yanes 1998 ).
In summary, PST has similar effects on glycogen, lipid metabolism and protein
synthesis stimulation than other insulin contrarregulatory hormones, like catechol-
amines, calcium dependent hormones or growth hormone. But, in addition, PST has
also been found to affect the expression of key genes in adipose tissue regulation. In
this line, PST is able to inhibit leptin expression up to 60%, an effect that is com-
pletely reversed if protein synthesis inhibitors are employed. In the same way PST
seems to enhance UCP2 expression, although the expression of other important
adipocyte genes, such PPAR gamma, or UCP-1 were not affected (Gonzalez-Yanes
and Sanchez-Margalet 2003 ).
3 Mechanisms of Action
3.1 In Hepatocytes
Molecular mechanisms of PST action in hepatocytes have been extensively studied
by our group. Thus, a cAMP-independent and a Ca2+−dose-dependent mechanism
has been observed in rat hepatocytes (Sanchez et al. 1992 ). The generation of inosi-
tol 1,4,5-triphosphate (IP3) is responsible for the mobilization of intracellular cal-
cium through a pertussis toxin-insensitive mechanism, while the activation of
calcium influx implicates a pertussis toxin-sensitive mechaism. In this line, phos-
pholipase C (PLC) has been found to be stimulated by PST in a dose-dependent
manner, producing an increase in the levels of IP3 and diacylglycerol (DAG) in rat
hepatocytes, leading to the activation of protein kinase C (PKC) (Sanchez-Margalet
and Goberna 1994a).
PST action is also mediated by cGMP production through a pertussis toxin-
sensitive G protein. Although the physiological role of cGMP in liver metabolism is
not yet fully understood, there are some studies confirming cGMP as a mediator of
N.E. Evtikhova et al.