The idea of personalised medicine was focused over the last years, which lead to a
growing interest in sex-specific research. Thereby regulation of steroidogenesis is
a central aspect. The liver has multiple functions, which can be realised simultaneously
only by zonation. Recent studies showed that Hedgehog (Hh) and Wnt/β-Catenin (Wnt)
signalling, two morphogenic pathways commonly associated with embryogenesis, development
and cancer are active in adult hepatocytes and act as master regulators of zonation
in the adult liver [1]. We investigate the specific role of those pathways in two
transgenic mouse models. One of them has an inactivated Hh signalling by a hepatocyte-specific
knockout (KO) of Smoothened, a key protein of the pathway [2]. The second model, APCloxPneo,
has an over-activated Wnt pathway due to partial reduced protein expression of its
major repressing element APC, which leads to an extended pericentral zone [1]. Surprisingly
we observed alterations in steroidogenesis gene expression in the transgenic mice;
yet it was assumed that steroidogenesis occurs in the liver only during embryogenesis
and is down-regulated afterwards. To verify which components of the signalling cascades
are involved in regulation of steroidogenesis, we performed different RNA interference
(KD) experiments in cultivated hepatocytes of C57BL/6N mice and quantified expression
levels by qRT-PCR.
So far we examined the expression of estrogen receptor (Esr1) and a couple of steroidogenesis
associated genes. The varying expression of Cyp17a1, a central regulator of steroidogenesis,
is conspicuous. Cyp17a1 expression is activated by estradiol incubation and significantly
correlates with Esr1 expression. In the APCloxPneo mouse model Cyp17a1 is significantly
down-regulated. However, no changes in steroidogenesis gene expression are observed
due to siRNA mediated Apc KD. In contrast, the Hh KO in hepatocytes results in increasing
Cyp17a1 expression, which is supported by equal results, provided by an in vitro KD
of Gli3, one of the transcription factors of active Hh signalling.
These results clearly demonstrate that Cyp17a1 expression in liver is controlled by
estradiol level and modulated by aberrant Wnt and Hh signalling. Thereby Hh pathway
seems to be the primary effector, while regulation by Wnt signalling may be indirectly
through altered Hh signalling. This is supported by further studies, showing that
modulation of one of the signalling pathways causes a time-delayed change in the other
one and vice versa. Thus, under pathological conditions the liver may acquire an important
role in altering systemic levels of steroid hormones, in particular since we found
no changes of Cyp17a1 expression in both, ovaries and kidney cortex of the Hh KO mice.
Further studies will focus on additional mechanistic details of the altered regulation
of steroidogenesis and are directed to reveal possible physiological consequences
of these unexpected changes.
References:
[1] Gebhardt & Matz-Soja, WJG, 2014
[2] Matz-Soja et al., CCS, 2014
Corresponding author: Rennert, Christiane
E-Mail:
christiane.rennert2@medizin.uni-leipzig.de
