TGF-β signaling and cholesterol: interdependent and druggable targets in NASH

目前针对非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）等多层次疾病的单一因素的治疗，由于治疗靶点可能相互依赖，注定会取得有限的成功。具体来说，在这些肝脏疾病的不同进展阶段，转化生长因子-β (TGF-β)信号和胆固醇在肝细胞的多个水平上有关联。然而，它们的相互依赖程度、机制联系以及对肝脏疾病结局的影响尚不清楚。我们在此提出一个跨学科合作项目，将德国和以色列的顶尖科学家结合在TGF-β信号，胆固醇/膜生物学及其在肝脏疾病中的作用方面具有独特和互补的专业知识。我们将采用跨学科的方法来解决TGF-β超家族（TβSF）配体（特别是TGF-β1）在NAFLD/NASH中的多层次信号调节，重点关注胆固醇的作用。我们的工作假设有三个方面：(i) nafld的进展涉及肝细胞对TGF-β刺激反应的改变。这些可能包括多个参数，包括TGF-β受体相互作用（复合物形成）、受体定位到膜微域、内吞噬、蛋白水解修饰（脱落）、外泌体转移以及通过Smad和非Smad途径下游TGF-β信号传导。（ii）胆固醇水平和体内平衡在NAFLD/NASH进展中发生改变，并可能在上述从受体结合到转录控制的步骤中调节对TGF-β刺激的反应。（iii）胆固醇/TGF-β信号共调控和相互作用参与肝细胞命运的决定，包括细胞应激、细胞死亡和自噬，从而诱导肝损伤，或存活和上皮-间质转化（EMT）介导癌变。

Current therapies directed towards single elements of multi-layered diseases like non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are destined to limited success due to possible interdependence of the therapeutic targets. Specifically, transforming growth factor-β (TGF-β) signaling and cholesterol were implicated at several levels in liver cells at different progression stages of these liver disorders. However, the degree of their interdependence, mechanistic linkage and implications for liver disease outcome are not known. We here propose a collaborative interdisciplinary project, combining leading scientists from Germany and Israel with distinct and complementary expertise in TGF-β signaling, cholesterol/membrane biology and their role in hepatic diseases. We will employ an interdisciplinary approach to tackle the multilayered regulation of signaling by TGF-β superfamily (TβSF) ligands, specifically TGF-β1, in NAFLD/NASH with focus on the role of cholesterol. Our working hypothesis has three aspects:(i) NAFLD progression involves alterations in hepatocellular responses to TGF-β stimuli. These may comprise multiple parameters, including TGF-β receptor interactions (complex formation), receptor localization to membrane microdomains, endocytosis, proteolytic modification (shedding), exosome transfer, and downstream TGF-β signaling via Smad and non-Smad pathways.(ii) Cholesterol levels and homeostasis are altered in NAFLD/NASH progression and may modulate the response to TGF-β stimuli at the aforementioned steps from receptor binding to transcriptional control.(iii) Cholesterol/TGF-β signaling co-regulation and interaction contribute to hepatocellular fate decisions towards cellular stress, cell death and autophagy, thus inducing liver damage, or survival and epithelial-to-mesenchymal transition (EMT) to mediate carcinogenesis.