Cooperation of Hedgehog and Wnt/β-Catenin signalling in regulation of steroidogenesis in the liver

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: [e-mail]