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.

中文翻译：

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环巴明和雷帕霉素协同抑制小鼠肝细胞中的 mTOR 信号传导，揭示 Hedgehog 和 mTor 信号传导在肝脏中的相互作用。


在肝脏中，能量稳态主要由雷帕霉素靶点（mTOR）信号传导调节，影响相关代​​谢途径，包括脂质代谢。然而，Hedgehog (Hh) 途径是新发现的肝脏脂质代谢驱动因素之一。尽管 mTOR 和 Hh 信号传导之间的联系先前已在癌症发生和进展中得到证实，但对它们在健康肝脏中的分子串扰的了解仍然缺乏。为了弥补这一信息差距，我们使用了转基因小鼠模型，该模型允许肝细胞特异性删除 Hh 通路，并进行体外研究以揭示 Hh 和 mTOR 信号传导之间的相互作用。该研究在雄性和雌性小鼠中进行，以调查这些信号通路串扰的性别差异。我们的结果表明，条件性 Hh 敲除减少了雌性小鼠原代肝细胞中线粒体三磷酸腺苷 (ATP) 的产生，并抑制了两性肝细胞的自噬。此外，体外研究表明，环巴明和雷帕霉素对雄性和雌性 C57BL/6N 小鼠原代肝细胞中 mTor 信号传导和氧化呼吸的抑制具有协同作用。总体而言，我们的结果表明 Hh 信号传导受损会影响 mTOR 信号传导，从而抑制氧化磷酸化和自噬。