Hormonal Programming / Imprinting
Phenomena as Related to the Liver
Goudochnikov V I*
Department Member of ISOAD, Brazil
Submission: November 12, 2022; Published: January 23, 2023
*Corresponding author: Viktor I Goudochnikov, Department Member of ISOAD, Santa Maria – RS, Brazil
How to cite this article: Goudochnikov V I*. Hormonal Programming / Imprinting
Phenomena as Related to the Liver
and Pancreas. J Endocrinol Thyroid Res. 2023; 7(2): 555707. DOI:10.19080/JETR.2023.07.555707
A short overview is presented on hormonal programming / imprinting phenomena in liver and pancreas. The main focus is made on some data related to the concept of DOHaD. It is proposed to enhance research efforts in this important area in the near future.
At present there are some suggestions explaining programming / imprinting phenomena for kidneys, heart and blood vessels (see discussion in) . However, for liver and pancreas the data are scarce, although the liver may be considered as principal metabolic “bioreactor” in human and animal body, whereas the pancreas has enormous significance in diabetology. Therefore, we decided to fill this lacune, also taking account of our previous experience with liver cell cultures. Preliminary evaluations of this topic for the liver have already been performed by us earlier [2,3].
In order to serve as candidates for mediators in mechanisms of programming / imprinting phenomena, the hormonal bioregulators must be able to affect target tissues in early development, preferably in perinatal period. We have studied hormonal effects in primary cultures of liver cells enriched by hepatocytes, obtained from fetal and prepubertal rats.
It was shown that glucocorticoids (GC) and thyroid hormone, insulin and growth hormone (GH) stimulated total RNA and protein biosynthesis already in cultured liver cells of fetal rats. Moreover, GC, insulin and GH stimulated the production of
immunoreactive serum albumin (SA) by these cells. With some exceptions, hormonal reactions of cultured liver cells obtained from prepubertal animals were similar to those in fetal rats [4-6].
All these data were obtained in parallel to seminal epidemiologic studies of David Barker and his colleagues. However, at that time we were not aware of these epidemiologic studies, since our goals were biochemical and pharmacologic ones, and not related to public health. Equally, we did not know about DOHaD concept, performing later similar age-related studies in primary cultures of anterior pituitary cells, nor during investigations of age-associated peculiarities of GC action on somatic and organ growth of rats in vivo. Only after being involved in epidemiologic studies in the first decade of current century were we able finally to re-evaluate our previous cell culture data on the basis of DOHaD paradigm.
Nevertheless, in at least one article about liver cells we have already mentioned the possibility of imprinting phenomenon, in order to interprete the absence of GC action on total RNA and protein biosynthesis after culturing in selective medium containing GC and barbiturate . However, later we tried to explain this phenomenon simply by possible elimination of Kupffer cells and therefore, the action of cytokines produced by them on
macromolecular synthesis in hepatocytes . It is important that
in the same work the effects of insulin and GH were preserved.
Moreover, later we were able to discover stimulatory action of
thyrotropin-releasing hormone (TRH) on total protein synthesis
in rat fetal liver cells grown in the same selective medium .
Of course, there exist another explanations for the above
mentioned absence of GC action, for example, down-regulation (or
desensitization) of GC receptors or stimulation of GC metabolism
by barbiturate included in selective medium. In any case, till the
present time cell culture techniques are not routinely used by
researchers in DOHaD area (with some rare exceptions, as in
). But our previous studies have already clearly shown the
maintenance in culture of somewhat like a “memory” about in vivo
situation by cells isolated from animals of different age groups
(see, e.g.) .
What about the interpretation of in vivo data related to DOHaD
First of all, there is a great difference in the effects of GC on
liver and anterior pituitary. In fact, GC inhibit DNA and total protein
biosynthesis in adenohypophyseal cells, but stimulate total RNA
and protein synthesis in liver cells in vitro. This corresponds well
to important role of the liver in production of serum proteins
including SA, as well as acute phase proteins. Moreover, GC
decrease protein synthesis and augment proteolysis in skeletal
muscles but stimulate transaminases and gluconeogenesis in the
However, the disadvantage of primary cultures is the
destruction of native tissues during cell isolation. For example,
the intact liver in adult animals and humans appears to have the
gradients of hepatocyte properties, according to tissue streaming
from putative stem or progenitor cells in periportal regions to
perivenous spaces. Probably, during perinatal programming /
imprinting such gradients are altered , causing predominance
of gluconeogenesis over glycogenesis , but this suggests that
hormonal mediators like GC may affect hepatic stem or progenitor
cells or the properties of tissue streaming.
Usually it is proposed that GC inhibit somatic and organ growth,
favoring cell differentiation and inhibiting cell proliferation.
However, in the liver a process of polyploidization should be also
considered with DNA replication without cytokinesis, one of the
principal reasons for us not to evaluate DNA synthesis in our
experiments on liver cell cultures as indicator of cell proliferation.
In addition, higher blood perfusion through the liver in
fetal period as a consequence of malnutrition may also affect
the gradients of hepatocyte properties in subsequent ontogeny
. Another possibility of liver involvement is alteration of the
production by hepatocytes of various hormone-binding proteins,
such as transcortin or corticosteroid-binding globulin (CBG),
several binding proteins for insulin-like growth factors (IGFBP)
etc. . All these suggestions await for adequate confirmation or
refusal in subsequent experimental studies.
One more disadvantage of primary cultures of rat liver cells
in our hands was the necessity of seeding cells on thin layer of
collagen isolated from rat tail tendons above the plastic bottom,
since native extracellular matrix probably would be able to
improve the functional activity of hepatocytes. It is interesting that
in experiments with selective medium we could obtain liver cell
cultures without collagen layer on the bottom, directly on plastic
treated only with bovine serum.
As referred to replicative senescence of other cell types, it
was already outlined that culture conditions, especially oxygen
content in atmosphere, and even some routine procedures like
subculturing or medium change may represent cell-stressing
factors that should be considered in evaluation and interpretation
of results obtained. However, in order to study hormonal regulation
of human progenitor or stem cells, bioethical barriers should be
overcome, probably, by means of using induced pluripotent stem
cells in culture (see discussions in) [16,17], therefore we have to
modify the culture conditions, in order to approximate them as
close as possible to embryonic intrauterine environment in vivo.
It appears that in prenatal period GC can inhibit beta-cell
development in pancreatic islets . On the other hand, lower
number of pancreatic beta-cells can result in relative glucose
overload in postnatal period, with higher risk of insulin resistance
and diabetes mellitus type 2 . Finally, GC may alter exocrine
development in the pancreas.
In conclusion, the liver may be different from other organs
where GC have generally catabolic action, however programming
/ imprinting phenomena in this organ are quite possible. Perhaps,
in order to reveal them, challenging tests like partial hepatectomy
should be performed. What for the pancreas, the attention should
be attracted to studying the possible programming / imprinting
phenomena of its exocrine part. In any case, researchers in DOHaD
area must pay much more attention to studies on hepatocytes and
pancreatic cells both in vivo and in vitro, considering enormous
amounts of data collected already for biochemistry, cell biology,
pharmacology etc. of the liver, as well as the importance of
pancreatic islet research in diabetology.
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