Ott Fritzi, Körner Christiane, Krohn Knut, Fischer Janett, Damm Georg, Seehofer Daniel, Berg Thomas, Matz-Soja Madlen
Faculty of Medicine, Rudolf Schönheimer Institute of Biochemistry, Leipzig University, Leipzig, Germany.
Division of Hepatology, Clinic and Polyclinic for Oncology, Gastroenterology, Hepatology, and Pneumology, University Hospital Leipzig, Leipzig, Germany.
Arch Toxicol. 2025 Mar;99(3):1105-1116. doi: 10.1007/s00204-024-03931-y. Epub 2024 Dec 23.
The Hedgehog (Hh) signaling pathway is essential for maintaining homeostasis during embryogenesis and in adult tissues. In the liver, dysregulation of this pathway often leads to liver cancer development. Recent studies also suggest that disturbances in the Hh pathway can affect liver metabolism in healthy livers through interactions with other signaling pathways, such as the Wnt/β-catenin pathway. As a result, the Hh pathway has emerged as a promising target for therapeutic intervention. However, little is known about the effects of Hh modulators on healthy hepatocytes. In our study, we investigated the effects of the Hh agonists SAG (300 nM) and triamcinolone acetonide (40 µM), as well as the antagonists RU-SKI 43 (100 nM), cyclopamine (5 µM), budesonide (25 µM), GANT61 (0.5 µM), and vismodegib (1 µM) on healthy mouse and human primary hepatocytes in vitro. We employed toxicological, transcriptomic, proteomic, and functional assays, including proliferation and Seahorse assays. Our results show that these compounds significantly impact metabolic pathways such as lipid and glucose metabolism at both transcriptional and protein levels. Mechanistically, our data suggest the involvement of both canonical and non-canonical Hedgehog pathways, a phenomenon not previously described in hepatocytes. These findings highlight the diverse effects of these compounds on signaling and key metabolic functions in the liver, which emphasizes the need to investigate the hepatic Hh cascade and its metabolic control in depth. As the compounds regulate different aspects of metabolism, they need to be carefully studied in appropriate model systems for specific therapeutic use.
刺猬信号通路（Hh）对于胚胎发育和成年组织维持体内平衡至关重要。在肝脏中，该信号通路失调常导致肝癌发生。近期研究还表明，Hh信号通路紊乱可通过与其他信号通路（如Wnt/β-连环蛋白信号通路）相互作用，影响健康肝脏的代谢。因此，Hh信号通路已成为有前景的治疗干预靶点。然而，关于Hh调节剂对健康肝细胞的影响知之甚少。在我们的研究中，我们研究了Hh激动剂SAG（300 nM）、曲安奈德（40 μM），以及拮抗剂RU-SKI 43（100 nM）、环杷明（5 μM）、布地奈德（25 μM）、GANT61（0.5 μM）和维莫德吉（1 μM）对健康小鼠和人原代肝细胞的体外影响。我们采用了毒理学、转录组学、蛋白质组学和功能分析，包括增殖和海马分析。我们的结果表明，这些化合物在转录和蛋白质水平上均显著影响脂质和葡萄糖代谢等代谢途径。从机制上讲，我们的数据表明经典和非经典刺猬信号通路均参与其中，这一现象此前在肝细胞中未曾描述过。这些发现突出了这些化合物对肝脏信号传导和关键代谢功能的多种影响，强调了深入研究肝脏Hh信号级联及其代谢调控的必要性。由于这些化合物调节代谢的不同方面，因此需要在适当的模型系统中对其进行仔细研究，以用于特定的治疗用途。
