Up and Down of Hedgehog Signaling leads to Down and Up of Steroidogenesis in the Liver

The liver is one of the largest organs in our organism with multiple anabolic and catabolic functions which can be carried out simultaneously only by zonation. Recent studies showed that the morphogenic signaling pathway Hedgehog, commonly associated with embryogenesis, development processes and cancer, is active in adult hepatocytes and act as master regulator of zonation in the adult liver (Gebhardt & Matz-Soja, WJG, 2014). Our goal is the investigation of the gender dimorphism of gene regulation in the liver. Thereby we surprisingly found a regulation of steroidogenesis associated genes in hepatocytes of transgenic mice with aberrant Hedgehog signaling; yet it was assumed that steroidogenesis occurs in the liver only during embryogenesis and is down-regulated afterwards.

We generated two transgenic mouse strains with an inactivated and constantly-activated Hedgehog signaling pathway, respectively. The first mouse strain has a hepatocyte-specific knockout of Smoothened (Smo), whereby the inhibition complex of the Gli transcription factors is continuously active, which results in an inactivated signaling cascade (SAC mice). The second strain has a hepatocyte-specific knockout of Patched1 (Ptch1) which lead to a permanently active Smo receptor whereby the inhibition complex of the Gli transcription factors is inactivated and the signaling cascade is continuously active (Ptch1LC1 mice).

We found, that a down-regulated Hedgehog pathway results in an up-regulation of some of the steroidogenic genes and vice versa. The enzymes Star and Cyp17a1, important for the first reactions of steroidogenesis and leading to DHEA formation, are up-regulated in SAC knockout mice and decreased in expression in Ptch1LC1 knockouts in comparison to wild types. The increased levels of DHEA may explain the infertility of the homozygous female SAC mice. If Ptch1LC1 mice have an improved reproduction remains unclear yet. In contrast, the hydroxysteroid dehydrogenases (Hsd3b1/2, Hsd17b2) are down-regulated in both mouse strains.

Collectively, the experiments showed a clear influence of the morphogenic Hedgehog pathway on the reproductive system and the regulation of steroidogenesis in the liver. These unexpected findings are promising for future studies to improve our understanding of the gender dimorphism of regulation in liver.

Corresponding author: Rennert, Christiane

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