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

Cells

卷:9

Thomas Berg¹  Erik Kolbe²  Carolin Lossius²  Robert Lehmann²  Fritzi Ott²  Luise Spormann²  Christiane Rennert²  Madlen Matz-Soja²  Rolf Gebhardt² 

[1] Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, Infectious Diseases, and Pneumology, University Clinic Leipzig, Liebigstr. 19, 04103 Leipzig, Germany;

[2] Rudolf-Schönheimer-Institute of Biochemistry, Faculty of Medicine, Leipzig University, Johannisallee 30, 04103 Leipzig, Germany;

关键词: mTOR;    hedgehog;    liver;    hepatocytes;    cyclopamine;    rapamycin;   

DOI  :  10.3390/cells9081817

来源: DOAJ

【 摘 要 】

In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

【 授权许可】

Unknown