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）等多层疾病的单一要素的治疗由于治疗靶点的可能相互依赖而注定成功有限。具体而言，在这些肝脏疾病的不同进展阶段，转化生长因子-β（TGF-β）信号传导和胆固醇在肝细胞中的几个水平上受到影响。然而，其相互依赖的程度，机制联系和对肝病结果的影响尚不清楚。我们在这里提出了一个跨学科的合作项目，结合来自德国和以色列的领先科学家在TGF-β信号传导，胆固醇/膜生物学及其在肝脏疾病中的作用方面的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中对信号传导的多层调节，重点关注胆固醇的作用。我们的工作假设有三个方面：（一） NAFLD进展涉及肝细胞对TGF-β刺激的反应的改变。这些可以包括多个参数，包括TGF-β受体相互作用（复合物形成）、受体定位于膜微结构域、内吞作用、蛋白水解修饰（脱落）、外泌体转移和经由Smad和非Smad途径的下游TGF-β信号传导。（二） 胆固醇水平和稳态在NAFLD/NASH进展中改变，并且可以在从受体结合到转录控制的上述步骤中调节对TGF-β刺激的响应。（三） 胆固醇/TGF-β信号共调节和相互作用有助于肝细胞对细胞应激、细胞死亡和自噬的命运决定，从而诱导肝损伤或存活和上皮向间充质转化（EMT）以介导癌发生。

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.