Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility

Abstract

The Hedgehog signaling pathway is known to be involved in embryogenesis, tissue remodeling, and carcinogenesis. Because of its involvement in carcinogenesis, it seems an interesting target for cancer therapy. Indeed, Sonidegib, an approved inhibitor of the Hedgehog receptor Smoothened (Smo), is highly active against diverse carcinomas, but its use is also reported to be associated with several systemic side effects. Our former work in adult mice demonstrated hepatic Hedgehog signaling to play a key role in the insulin-like growth factor axis and lipid metabolism. The current work using mice with an embryonic and hepatocyte-specific Smo deletion describes an adverse impact of the hepatic Hedgehog pathway on female fertility. In female SAC-KO mice, we detected androgenization characterized by a 3.3-fold increase in testosterone at 12 weeks of age based on an impressive induction of steroidogenic gene expression in hepatocytes, but not in the classic steroidogenic organs (ovary and adrenal gland). Along with the elevated level of testosterone, the female SAC-KO mice showed infertility characterized by juvenile reproductive organs and acyclicity. The endocrine and reproductive alterations resembled polycystic ovarian syndrome and could be confirmed in a second mouse model with conditional deletion of Smo at 8 weeks of age after an extended period of 8 months. We conclude that the down-regulation of hepatic Hedgehog signaling leads to an impaired hormonal balance by the induction of steroidogenesis in the liver. These effects of Hedgehog signaling inhibition should be considered when using Hedgehog inhibitors as anti-cancer drugs.

Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

“…Therefore, we conducted most of the experiments in this study in both male and female mice to examine possible sex-specific differences in the Hh and mTOR signalling pathways. As was previously observed, the Hh pathway influences the development of sexual organs by regulating androgen metabolism [48][49][50]. Therefore, it appears obvious that Hh also regulates other pathways in a sex-specific manner.…”

Tick-tock hedgehog-mutual crosstalk with liver circadian clock promotes liver steatosis

“…Compared to other organs, the widespread contribution of Hh signaling to the regulation of liver metabolism in healthy mature animals has been ignored for quite some time. 25,26 Here, in a proof of principle study, we show that Hh signaling regulates liver metabolism in close cooperation with the liver circadian clock to maintain metabolic homeostasis.…”

The Diurnal Timing of Starvation Differently Impacts Murine Hepatic Gene Expression and Lipid Metabolism – A Systems Biology Analysis Using Self-Organizing Maps

“…The timing and length of the starvation period used by different groups may explain these diverse results and illustrate the importance of our study. Steroid hormone synthesis is generally localized in the gonads and adrenal glands, but the adult liver also performs steroidogenesis under specific conditions ( Grasfeder et al, 2009 ; Rennert et al, 2017 ). Cyp17a1 expression, which is a central steroidogenic enzyme, was induced following evening starvation.…”